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**Chapter 4**

**Provisional chapter**

**Pharmacologic Interventions for Preventing**

**Pharmacologic Interventions for Preventing**

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.73174

**Osteoarthritis**

**Osteoarthritis**

Charles J. Malemud

Charles J. Malemud

**Abstract**

**1. Introduction**

**Chondrocyte Apoptosis in Rheumatoid Arthritis and**

**Chondrocyte Apoptosis in Rheumatoid Arthritis and**

Chronic inflammation drives the progression of rheumatoid arthritis (RA) and osteoarthritis (OA) to synovial joint failure. The inflammatory state in both musculoskeletal diseases is associated with significantly elevated levels of pro-inflammatory cytokines in joint synovial fluid, which is best exemplified by increases in interleukin-1β (IL-1β), IL-6, IL-17, tumor necrosis factor-α, among others, as well as increased activity of soluble mediators such as nitric oxide and certain growth factors including vascular endothelial growth factor and fibroblast growth factor. The multitude of these factors activate chondrocyte signal transduction pathways resulting in programmed cell death, otherwise known as apoptosis as well as compromising chondrocyte autophagy. Importantly, chondrocyte apoptosis causes a loss of articular cartilage vitality which dampens cartilage repair mechanisms because at present, the possibility that chondrocyte progenitor cells could replace those differentiated chondrocytes lost via apoptosis remains debatable. Certain pharmacologic interventions which have been proven to induce apoptosis in various cancer cell studies *in vitro* suggest the possibility that drugs could be developed to specifically suppress or completely inhibit chondrocyte apoptosis in RA and OA cartilage. This review supports that contention and indicates that apoptosis can be inhibited by identifying novel cellular targets which promote apoptosis and autophagy. **Keywords:** apoptosis, chondrocyte, osteoarthritis, rheumatoid arthritis, signal transduction

> © 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

Controlled cell death otherwise known as programmed cell death or apoptosis constitutes a critical event which is germane to the normal development of the immune system, the appropriate

DOI: 10.5772/intechopen.73174

#### **Pharmacologic Interventions for Preventing Chondrocyte Apoptosis in Rheumatoid Arthritis and Osteoarthritis Pharmacologic Interventions for Preventing Chondrocyte Apoptosis in Rheumatoid Arthritis and Osteoarthritis**

DOI: 10.5772/intechopen.73174

Charles J. Malemud Charles J. Malemud

[94] Hussain MM, Rava P, Pan X, Dai K, Dougan SK, Iqbal J, et al. Microsomal triglyceride transfer protein in plasma and cellular lipid metabolism. Current Opinion in

[95] Libri V, Brown AP, Gambarota G, Haddad J, Shields GS, Dawes H, et al. A pilot randomized, placebo controlled, double blind phase I trial of the novel SIRT1 activator

[96] Troke RC, Tan TM, Bloom SR. The future role of gut hormones in the treatment of obe-

[97] Campbell JE, Drucker DJ. Islet α cells and glucagon--critical regulators of energy

[98] Müller TD, Sullivan LM, Habegger K, Yi CX, Kabra D, Grant E, et al. Restoration of leptin responsiveness in diet-induced obese mice using an optimized leptin analog in combination with exendin-4 or FGF21. Journal of Peptide Science. 2012;**18**(6):383-393

[99] Heal DJ, Gosden J, Smith SL. A review of late-stage CNS drug candidates for the treat-

[100] Khera R, Murad MH, Chandar AK, Dulai PS, Wang Z, Prokop LJ, et al. Association of pharmacological treatments for obesity with weight loss and adverse events: A systematic review and meta-analysis. Journal of the American Medical Association.

[101] Leibel RL, Seeley RJ, Darsow T, Berg EG, Smith SR, Ratner R. Biologic responses to weight loss and weight regain: Report from an American Diabetes Association Research

[102] Krentz AJ, Fujioka K, Hompesch M. Evolution of pharmacological obesity treatments: Focus on adverse side-effect profiles. Diabetes, Obesity & Metabolism. 2016;**18**(6):558-570

[103] Sadry SA, Drucker DJ. Emerging combinatorial hormone therapies for the treatment of

obesity and T2DM. Nature Reviews. Endocrinology. 2013;**9**(7):425-433

SRT2104 in elderly volunteers. PLoS One. 2012;**7**(12):e51395

sity. Therapeutic Advances in Chronic Disease. 2014;**5**(1):4-14

homeostasis. Nature Reviews. Endocrinology. 2015;**11**(6):329-338

ment of obesity. International Journal of Obesity. 2013;**37**(1):107-117

Lipidology. 2008;**19**(3):277-284

76 Drug Discovery - Concepts to Market

2016;**315**(22):2424-2434

Symposium. Diabetes. 2015;**64**(7):2299-2309

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.73174

#### **Abstract**

Chronic inflammation drives the progression of rheumatoid arthritis (RA) and osteoarthritis (OA) to synovial joint failure. The inflammatory state in both musculoskeletal diseases is associated with significantly elevated levels of pro-inflammatory cytokines in joint synovial fluid, which is best exemplified by increases in interleukin-1β (IL-1β), IL-6, IL-17, tumor necrosis factor-α, among others, as well as increased activity of soluble mediators such as nitric oxide and certain growth factors including vascular endothelial growth factor and fibroblast growth factor. The multitude of these factors activate chondrocyte signal transduction pathways resulting in programmed cell death, otherwise known as apoptosis as well as compromising chondrocyte autophagy. Importantly, chondrocyte apoptosis causes a loss of articular cartilage vitality which dampens cartilage repair mechanisms because at present, the possibility that chondrocyte progenitor cells could replace those differentiated chondrocytes lost via apoptosis remains debatable. Certain pharmacologic interventions which have been proven to induce apoptosis in various cancer cell studies *in vitro* suggest the possibility that drugs could be developed to specifically suppress or completely inhibit chondrocyte apoptosis in RA and OA cartilage. This review supports that contention and indicates that apoptosis can be inhibited by identifying novel cellular targets which promote apoptosis and autophagy.

**Keywords:** apoptosis, chondrocyte, osteoarthritis, rheumatoid arthritis, signal transduction

#### **1. Introduction**

Controlled cell death otherwise known as programmed cell death or apoptosis constitutes a critical event which is germane to the normal development of the immune system, the appropriate

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

integration of cells within tissues and organs and organ homeostasis [1–7]. However, the aberrant frequency of apoptotic cells can compromise normal tissue architecture and, in doing so, contribute to the loss of cell vitality [8–10]. This is especially the case in explaining the loss of chondrocyte viability in arthritic conditions of synovial joints, such as rheumatoid arthritis (RA) and osteoarthritis (OA).

some time during the course of the progression of OA, immune-mediated inflammation may also cause a similar chronic inflammatory microenvironment, as found in RA, to arise and persist in OA synovial tissue [55] resulting, in part, in an increased frequency of apop-

Pharmacologic Interventions for Preventing Chondrocyte Apoptosis in Rheumatoid Arthritis…

http://dx.doi.org/10.5772/intechopen.73174

79

Analyses of synovial fluids and sera from RA and OA patients with active disease showed that these samples contained significantly elevated levels of various pro-inflammatory cytokines and growth factors when compared to a control group [52–68]. Of note, incubation of rat [69], non-arthritic or human chondrocytes from OA cartilage [70–76] or immortalized lines of human chondrocytes [77] with physiological levels of these cytokines, growth factors (e.g., VEGF and FGF) or additional soluble mediators (e.g., nitric oxide) were shown to induce apoptosis, which was accompanied by activation of SAPK/MAPK, JAK/STAT or PI3K/Akt/mTor signaling in these cells [78–81]. In addition, mediators of inflamma-

in perpetuating chronic inflammation [38]. The induction of apoptosis was also shown to be related to altered levels of various down-regulators of apoptosis. These included BCL-2-like protein-11 (Bim) [18], B-cell lymphoma-2 (Bcl-2) [75], cell-derived inhibitors of apoptosis proteins (IAPs) [81–84] and Suppressor of Cytokine Synthesis (SOCS) [85, 86]. Furthermore, alterations in the functions of mitochondria [87] and endoplasmic reticulum (ER) [88–91] related to cell stress, the generation of reactive oxygen species [92] and the recently described advanced oxidation protein products [93] with respect to their capacity to induce apoptosis were reported as well. Taken together, these results provided compelling evidence that pro-inflammatory cytokines, growth factors and soluble mediators germane to the progression of RA and OA are responsible for inducing chondrocyte apoptosis

A recent review of RA pathogenesis by Angelotti et al. [94] emphasized the view that numerous cells comprising the innate immune system, including macrophages, dendritic cells, mast cells, natural killer cells and neutrophils as well as T-cells and B-cells, regulators of adaptive immunity, are primarily responsible for perpetuating the state of chronic inflammation through their capacity to alter the survival of resident synovial fibroblasts. It is also likely that such cell combinations are also involved in the progression of OA as well, as evidenced by the skewing of cartilage homeostasis toward catabolism, and the loss of chondrocyte vitality via the induction of apoptosis [95–97]. However, it was previously shown that the classical apoptosis cascade can be activated by various pro-inflammatory cytokines, and certain growth factors, chemokines, chemokine receptors (**Table 1**) and other interleukins, including

and neuropeptides (e.g., Substance P), are also implicated

**2. Compelling evidence that many factors relevant to RA and OA**

**promote or induce chondrocyte apoptosis** *in vitro*

**3. The relationship between apoptosis and autophagy**

totic chondrocytes [60].

tion, including prostaglandin E2

in these conditions.

Significant progress has been achieved over the previous decade or so in furthering our understanding of the cellular and molecular events that trigger the increased frequency of chondrocyte apoptosis in RA and OA [11–16]. These advances include (1) an appreciation that the significant increase in the levels of pro-inflammatory cytokines in synovial fluid from RA and OA patients also can induce chondrocyte apoptosis *in vitro* [17–21]; (2) that the elevated frequency of chondrocyte apoptosis by these cytokines is deregulated by altered signal transduction which can involve continuous activation of stress-activated/mitogen-activated protein kinases (SAPK/MAPK) [22–25], the Janus kinase/Signal Transducers and Activators of Transcription (JAK/STAT) pathway [26–31], the phosphatidylinositide-3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway [32–36], and other protein kinase pathways [37–40]; (3) that specific co-factors are capable of regulating the activation of these signaling pathways [41–44]; and (4) that micro-RNAs (mi-RNAs) can regulate the activity of these co-factors and, in this manner, control the induction of apoptosis via these signaling pathways [45–48].

Furthermore, the increased frequency of chondrocyte apoptosis now confirmed in guinea pig OA cartilage [49] as well as human RA and OA articular cartilage [50–53] presents a particularly onerous scenario for the survival of synovial joints under these conditions. Although a population of chondroprogenitor cells was identified in several studies of adult normal and diseased articular cartilage [54–56], significant repair of damaged articular cartilage in RA and OA by these cells is effete. This effect on cartilage repair may result from elevated levels of pro-inflammatory cytokines such as IL-17, which was recently shown to inhibit the chondrocyte maturation lineage emanating from progenitor cells in RA [57]. Therefore, even if chondrocyte precursor cells exist in adult articular cartilage which could potentially become authentic chondrocytes lost from articular cartilage via apoptosis or chondrocytes lost via diffusion of cartilage extracellular matrix fragments into synovial fluid, the reduction in chondrocyte vitality via apoptosis would be a challenging event to overcome, especially in a synovial joint microenvironment replete with pro-inflammatory cytokines.

In this chapter, we have systematically examined the mechanistic underpinning for identifying novel targets in order to suppress or even inhibit chondrocyte apoptosis in RA and OA. However, the scenario in RA, in particular, is even more complex than in OA because in the context of devising therapeutic strategies designed to inhibit chondrocyte apoptosis in RA, one must also take into account the fact that in the hyperplastic RA synovial tissue, comprised of activated synoviocytes, immune cells, macrophages and other inflammatory cells are generally considered to be relatively "apoptosis-resistant" [58, 59]. Thus, this characteristic of the RA joint ensures a plentiful source of immune-mediated cells and non-immune inflammatory cells which drive the progression of RA. It is also likely that at some time during the course of the progression of OA, immune-mediated inflammation may also cause a similar chronic inflammatory microenvironment, as found in RA, to arise and persist in OA synovial tissue [55] resulting, in part, in an increased frequency of apoptotic chondrocytes [60].

### **2. Compelling evidence that many factors relevant to RA and OA promote or induce chondrocyte apoptosis** *in vitro*

integration of cells within tissues and organs and organ homeostasis [1–7]. However, the aberrant frequency of apoptotic cells can compromise normal tissue architecture and, in doing so, contribute to the loss of cell vitality [8–10]. This is especially the case in explaining the loss of chondrocyte viability in arthritic conditions of synovial joints, such as rheumatoid arthritis (RA)

Significant progress has been achieved over the previous decade or so in furthering our understanding of the cellular and molecular events that trigger the increased frequency of chondrocyte apoptosis in RA and OA [11–16]. These advances include (1) an appreciation that the significant increase in the levels of pro-inflammatory cytokines in synovial fluid from RA and OA patients also can induce chondrocyte apoptosis *in vitro* [17–21]; (2) that the elevated frequency of chondrocyte apoptosis by these cytokines is deregulated by altered signal transduction which can involve continuous activation of stress-activated/mitogen-activated protein kinases (SAPK/MAPK) [22–25], the Janus kinase/Signal Transducers and Activators of Transcription (JAK/STAT) pathway [26–31], the phosphatidylinositide-3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway [32–36], and other protein kinase pathways [37–40]; (3) that specific co-factors are capable of regulating the activation of these signaling pathways [41–44]; and (4) that micro-RNAs (mi-RNAs) can regulate the activity of these co-factors and, in this manner, control the induction of apoptosis via these signaling

Furthermore, the increased frequency of chondrocyte apoptosis now confirmed in guinea pig OA cartilage [49] as well as human RA and OA articular cartilage [50–53] presents a particularly onerous scenario for the survival of synovial joints under these conditions. Although a population of chondroprogenitor cells was identified in several studies of adult normal and diseased articular cartilage [54–56], significant repair of damaged articular cartilage in RA and OA by these cells is effete. This effect on cartilage repair may result from elevated levels of pro-inflammatory cytokines such as IL-17, which was recently shown to inhibit the chondrocyte maturation lineage emanating from progenitor cells in RA [57]. Therefore, even if chondrocyte precursor cells exist in adult articular cartilage which could potentially become authentic chondrocytes lost from articular cartilage via apoptosis or chondrocytes lost via diffusion of cartilage extracellular matrix fragments into synovial fluid, the reduction in chondrocyte vitality via apoptosis would be a challenging event to overcome, especially in a synovial joint microenvironment replete with pro-inflammatory

In this chapter, we have systematically examined the mechanistic underpinning for identifying novel targets in order to suppress or even inhibit chondrocyte apoptosis in RA and OA. However, the scenario in RA, in particular, is even more complex than in OA because in the context of devising therapeutic strategies designed to inhibit chondrocyte apoptosis in RA, one must also take into account the fact that in the hyperplastic RA synovial tissue, comprised of activated synoviocytes, immune cells, macrophages and other inflammatory cells are generally considered to be relatively "apoptosis-resistant" [58, 59]. Thus, this characteristic of the RA joint ensures a plentiful source of immune-mediated cells and non-immune inflammatory cells which drive the progression of RA. It is also likely that at

and osteoarthritis (OA).

78 Drug Discovery - Concepts to Market

pathways [45–48].

cytokines.

Analyses of synovial fluids and sera from RA and OA patients with active disease showed that these samples contained significantly elevated levels of various pro-inflammatory cytokines and growth factors when compared to a control group [52–68]. Of note, incubation of rat [69], non-arthritic or human chondrocytes from OA cartilage [70–76] or immortalized lines of human chondrocytes [77] with physiological levels of these cytokines, growth factors (e.g., VEGF and FGF) or additional soluble mediators (e.g., nitric oxide) were shown to induce apoptosis, which was accompanied by activation of SAPK/MAPK, JAK/STAT or PI3K/Akt/mTor signaling in these cells [78–81]. In addition, mediators of inflammation, including prostaglandin E2 and neuropeptides (e.g., Substance P), are also implicated in perpetuating chronic inflammation [38]. The induction of apoptosis was also shown to be related to altered levels of various down-regulators of apoptosis. These included BCL-2-like protein-11 (Bim) [18], B-cell lymphoma-2 (Bcl-2) [75], cell-derived inhibitors of apoptosis proteins (IAPs) [81–84] and Suppressor of Cytokine Synthesis (SOCS) [85, 86]. Furthermore, alterations in the functions of mitochondria [87] and endoplasmic reticulum (ER) [88–91] related to cell stress, the generation of reactive oxygen species [92] and the recently described advanced oxidation protein products [93] with respect to their capacity to induce apoptosis were reported as well. Taken together, these results provided compelling evidence that pro-inflammatory cytokines, growth factors and soluble mediators germane to the progression of RA and OA are responsible for inducing chondrocyte apoptosis in these conditions.

#### **3. The relationship between apoptosis and autophagy**

A recent review of RA pathogenesis by Angelotti et al. [94] emphasized the view that numerous cells comprising the innate immune system, including macrophages, dendritic cells, mast cells, natural killer cells and neutrophils as well as T-cells and B-cells, regulators of adaptive immunity, are primarily responsible for perpetuating the state of chronic inflammation through their capacity to alter the survival of resident synovial fibroblasts. It is also likely that such cell combinations are also involved in the progression of OA as well, as evidenced by the skewing of cartilage homeostasis toward catabolism, and the loss of chondrocyte vitality via the induction of apoptosis [95–97]. However, it was previously shown that the classical apoptosis cascade can be activated by various pro-inflammatory cytokines, and certain growth factors, chemokines, chemokine receptors (**Table 1**) and other interleukins, including IL-8 (CXCL8) and adhesion molecules [64]. Thus, these factors are likely to be the most influential in inducing apoptosis pathway RA. However, a non-classical form of apoptosis, termed, "chondroptosis" is just as likely to be activated in OA. In that regard, "chondroptosis" involves an increase in the number of ER and Golgi apparatus reflecting an increase in protein synthesis that accompanies the loss of viable chondrocytes [98].

deletion of mTOR resulted in the up-regulation of autophagy [102]. Autophagy protected mouse cartilage from degeneration [109]. Autophagy was also shown to protect chondrocytes from glucocorticoid-induced apoptosis via reactive oxygen species, Akt and FOXO3 signaling [110] as well as from advanced glycation end-product-induced apoptosis which was accompa-

Pharmacologic Interventions for Preventing Chondrocyte Apoptosis in Rheumatoid Arthritis…

http://dx.doi.org/10.5772/intechopen.73174

81

Micro-RNAs (miRs) are critical mediators of mRNA degradation as well acting as repressors of translation. MiRs have been implicated in the development of skeletal long bones via their multiple effects on osteogenesis [112]. However, recent evidence has also improved the recognized role of miRs in RA pathology as a result of evidence that many miRs including miR-16, miR-146a/b, miR-150, miR-155 and miR-223 are over-expressed both in the peripheral circulation of RA patients and in the RA synovial joint [113], although other miRs relevant to RA, such as miR-21, miR-125a, miR-223, and miR-451 are principally found to be at elevated

Additional evidence has been presented to show that several of these miRs also regulate apoptosis. For example, the level of the pro-apoptotic protein, Bim, was increased when activated T-cells were incubated with a repressor of miR-148a resulting in an increase in the Th1 apoptotic response [114]. Thus, accumulating evidence showed that both the immune cells and chondrocyte apoptotic and autophagic response can be manipulated by either experimental overexpression or repression of various miRs which are relevant to OA [115] and RA [116] pathophysiology. The results of numerous studies have confirmed the role of specific miRs as directly affecting apoptosis or indirectly affecting apoptosis through their activity on other molecules that regulate chondrocyte apoptosis. For example, mIR-146a was reported to be over-expressed in OA [117]. In that regard, mIR-146a was shown to promote human OA chondrocyte proliferation and to inhibit apoptosis by targeting tumor necrosis factor receptor-associated factor 6 (TRAF6) via NF-κB [118, 119]. By contrast, mIR-146a was also shown to target IL-1β, to induce VEGF production, and to promote rat chondrocyte apoptosis via Smad4 [120]. On the other hand, silencing of miR-34a inhibited rat chondrocyte apoptosis [121], whereas overexpression of mIR-34a promoted apoptosis in normal human chondrocytes by targeting SIRT1/p53 signaling [122], although other evidences indicated that miR-34a was increased in intervertebral disc degeneration and was associated with an elevated frequency of apoptotic cartilage end plate chondrocytes [123]. In another study, glycerol-3-phosphate dehydrogenase 1-like protein was shown to be a target for mIR-181a, which is deregulated in OA wherein human chondrocyte apoptosis was increased [124]. In yet another study, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) [36] was identified as the target for mIR-181 whereby mIR-181 up-regulated the expression of proteins associated with apoptosis, including caspase-3 and PARP. However, mIR-181 also up-regulated MMP-2 (gelatinase A; 72 kDa gelatinase) and MMP-9 (gelatinase B; 92 kDa gelatinase) [125] which are two MMPs directly relevant to

nied by lower levels of MMP-3 and MMP-13 in rat chondrocyte cultures [111].

levels in the plasma and sera of RA patients.

cartilage matrix protein degradation in arthritis [126].

**4. Do micro-RNAs play a critical role in chondrocyte apoptosis?**

Furthermore, changes in the number of viable articular chondrocytes in experimentally induced arthritis [99], human RA [100], and OA are almost certainly associated with the autophagicmediated cell death of chondrocytes [101–105], which occurs in concert with the activation of the extrinsic apoptosis pathway, the latter mediated by Tumor necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL), Death Receptor-5 (DR5) and caspase-3 [106, 107]. In that regard, it was noteworthy that Huang etal. [108] reported that exogenous leptin promoted chondrocyte apoptosis while inhibiting chondrocyte autophagy via the up-regulation of lysyl oxidase-like 3 (LOXL3). Thus, in their study [108], overexpression of LOXL3 inhibited chondrocyte autophagy by activating mechanistic target of rapamycin complex-1 (mTORC1) [36]. In contrast, cartilage-specific

3 Fibroblast growth factor.

4 Macrophage inflammatory protein-1 (CCL3).

5 Growth-related oncogene-α.

6 GRO-βγ.

7 Monocyte chemotactic protein-1.

8 Regulated on activation, normal T-cell expressed and secreted.

**Table 1.** Cytokines, chemokines, chemokine receptors and growth factors in RA and OA.

deletion of mTOR resulted in the up-regulation of autophagy [102]. Autophagy protected mouse cartilage from degeneration [109]. Autophagy was also shown to protect chondrocytes from glucocorticoid-induced apoptosis via reactive oxygen species, Akt and FOXO3 signaling [110] as well as from advanced glycation end-product-induced apoptosis which was accompanied by lower levels of MMP-3 and MMP-13 in rat chondrocyte cultures [111].

### **4. Do micro-RNAs play a critical role in chondrocyte apoptosis?**

IL-8 (CXCL8) and adhesion molecules [64]. Thus, these factors are likely to be the most influential in inducing apoptosis pathway RA. However, a non-classical form of apoptosis, termed, "chondroptosis" is just as likely to be activated in OA. In that regard, "chondroptosis" involves an increase in the number of ER and Golgi apparatus reflecting an increase in protein synthesis

Furthermore, changes in the number of viable articular chondrocytes in experimentally induced arthritis [99], human RA [100], and OA are almost certainly associated with the autophagicmediated cell death of chondrocytes [101–105], which occurs in concert with the activation of the extrinsic apoptosis pathway, the latter mediated by Tumor necrosis Factor-Related Apoptosis-Inducing Ligand (TRAIL), Death Receptor-5 (DR5) and caspase-3 [106, 107]. In that regard, it was noteworthy that Huang etal. [108] reported that exogenous leptin promoted chondrocyte apoptosis while inhibiting chondrocyte autophagy via the up-regulation of lysyl oxidase-like 3 (LOXL3). Thus, in their study [108], overexpression of LOXL3 inhibited chondrocyte autophagy by activating mechanistic target of rapamycin complex-1 (mTORC1) [36]. In contrast, cartilage-specific

**Cytokine, chemokine, chemokine receptors and growth factors Reference** IL-17, IL-18BP [62] IL-17, IL-20, IL-21 [63] IL-7 [64] IL-12/IL-23 [64] IL-15/IL-16 [64] IL-17/IL-18 [64] IL-19/-20/-21 [64] IL-32 [64]

; Leptin; FGF3 [64–66]

(CXCL1); GRO-βγ6

; MCP-17

; RANTES8 ; [65, 68]

; GRO-α5

IL-6 [64, 67, 68] TNF-α [64, 67, 69] IL-1β [64]

that accompanies the loss of viable chondrocytes [98].

80 Drug Discovery - Concepts to Market

VEGF1

Eotaxin-1

1

2

3

4

5

6 GRO-βγ. 7

8

; TGF-β1 2

CXCR3; CXCR4,-5; CXCR-1,-5,-6; IL-8; MIP-1α4

.

Regulated on activation, normal T-cell expressed and secreted.

**Table 1.** Cytokines, chemokines, chemokine receptors and growth factors in RA and OA.

Vascular endothelial growth factor.

Macrophage inflammatory protein-1 (CCL3).

Transforming growth factor-β1

Fibroblast growth factor.

Growth-related oncogene-α.

Monocyte chemotactic protein-1.

Micro-RNAs (miRs) are critical mediators of mRNA degradation as well acting as repressors of translation. MiRs have been implicated in the development of skeletal long bones via their multiple effects on osteogenesis [112]. However, recent evidence has also improved the recognized role of miRs in RA pathology as a result of evidence that many miRs including miR-16, miR-146a/b, miR-150, miR-155 and miR-223 are over-expressed both in the peripheral circulation of RA patients and in the RA synovial joint [113], although other miRs relevant to RA, such as miR-21, miR-125a, miR-223, and miR-451 are principally found to be at elevated levels in the plasma and sera of RA patients.

Additional evidence has been presented to show that several of these miRs also regulate apoptosis. For example, the level of the pro-apoptotic protein, Bim, was increased when activated T-cells were incubated with a repressor of miR-148a resulting in an increase in the Th1 apoptotic response [114]. Thus, accumulating evidence showed that both the immune cells and chondrocyte apoptotic and autophagic response can be manipulated by either experimental overexpression or repression of various miRs which are relevant to OA [115] and RA [116] pathophysiology.

The results of numerous studies have confirmed the role of specific miRs as directly affecting apoptosis or indirectly affecting apoptosis through their activity on other molecules that regulate chondrocyte apoptosis. For example, mIR-146a was reported to be over-expressed in OA [117]. In that regard, mIR-146a was shown to promote human OA chondrocyte proliferation and to inhibit apoptosis by targeting tumor necrosis factor receptor-associated factor 6 (TRAF6) via NF-κB [118, 119]. By contrast, mIR-146a was also shown to target IL-1β, to induce VEGF production, and to promote rat chondrocyte apoptosis via Smad4 [120]. On the other hand, silencing of miR-34a inhibited rat chondrocyte apoptosis [121], whereas overexpression of mIR-34a promoted apoptosis in normal human chondrocytes by targeting SIRT1/p53 signaling [122], although other evidences indicated that miR-34a was increased in intervertebral disc degeneration and was associated with an elevated frequency of apoptotic cartilage end plate chondrocytes [123]. In another study, glycerol-3-phosphate dehydrogenase 1-like protein was shown to be a target for mIR-181a, which is deregulated in OA wherein human chondrocyte apoptosis was increased [124]. In yet another study, phosphatase and tensin homolog deleted on chromosome 10 (PTEN) [36] was identified as the target for mIR-181 whereby mIR-181 up-regulated the expression of proteins associated with apoptosis, including caspase-3 and PARP. However, mIR-181 also up-regulated MMP-2 (gelatinase A; 72 kDa gelatinase) and MMP-9 (gelatinase B; 92 kDa gelatinase) [125] which are two MMPs directly relevant to cartilage matrix protein degradation in arthritis [126].

Of note, several miRs were identified as potential targets for inducing chondrocyte survival and therefore could be considered anti-apoptosis factors; these included mIR-98 [127–129], mIR-9 [130], mIR-15a-5p [131], mIR-142-3p [132] and mIR-502-5p [133]. Additional mIRs, exemplified by miR-195 [134], mIR-139 [135], mIR-29b-3p [136], mIR-488-3p [137] and mIR-203 [138] could very well be included in this group. For example, by employing the C28/I2 line of immortalized human chondrocytes, Zhao et al. [138] showed that knockdown of mIR-203 targeting the myeloid cell leukemia-1 (MCL-1) protein activated Wnt/β-catenin and JAK/ STAT signaling promoted chondrocyte survival.

the frequency of apoptotic chondrocytes along with NO-induced NF-κB, p53 and caspase-3 [141]. IL-1β, another potent inducer of chondrocyte apoptosis, was also shown to be JNKdependent as both chemical inhibitors of JNK as well as RNA interference with Bim, the latter up-regulated by IL-1β, were shown to be phosphorylated-JNK-dependent [142]. In other studies, chondrocyte apoptosis was again linked to IL-1β-induced activation of p38 kinase [143–145], along with JNK [145], and MMP-3 gene expression with IL-1β negatively regulating chondrocyte autophagy [145]. Of note, AG490, a pan-JAK SMI significantly reduced leptininduced chondrocyte apoptosis *in vitro* as well as reducing STAT3 phosphorylation, reactive oxygen species, MMP-13 and B-cell lymphoma 2-associated X protein [146]. Interestingly, Li et al. [147] showed that the PI3K/NF-κB pathway was activated by TNF-α in human chondrocytes. However, the effect of leptin did not involve mTOR, suggesting that newly developed small molecule mTOR inhibitors (reviewed in [36]) might not be useful for neutralizing acti-

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Several attempts to employ various compounds and/or natural products to inhibit chondrocyte apoptosis have taken advantage of various findings related to the role of these compounds and natural products in many of the aforementioned signal transduction pathways. For example, IL-1β-induced chondrocyte apoptosis was inhibited by oligomeric proanthocyanidin, a water-soluble plant polyphenolic compound [148]. Thus, the over-expression of peroxiredoxin 4 (PRDX4), a member of the PRDX family (a molecule essential for scavenging free radicals and reducing reactive oxygen species) reduced IL-1β-induced rat chondrocyte apoptosis [149]. Importantly, AZD5363, an inhibitor of Akt activation also reduced the apoptosis protective effect of PRDX4. In another aspect, chondrocyte apoptosis induced by IL-1β not only involved reduced Bcl-2 levels, activated (i.e., phosphorylated) Akt, and activated PRAS40, a proline-rich 40 kDa Akt substrate and an inhibitor of mTORC1 kinase activity, but

Shikonin, a compound with anti-tumor, anti-inflammatory, anti-viral and pharmacological efficacy significantly inhibited apoptosis by decreasing IL-1β, TNF-α and inducible NO synthase (iNOS) in rats with experimentally induced OA [150]. The effect of shikonin in this animal model of OA was accompanied not only by reduced caspase-3 and cyclooxygenase-2 activity but also by increased activation of Akt, indicating a prominent role for PI3K/Akt signaling in this rat model of OA. Finally, a few novel targets, including protein kinase R-like endoplasmic reticulum kinase and activating transcription factor 6, were identified as potent regulators of chondrocyte apoptosis *in vitro* and *in vivo* [151], although the precise signaling

Several experimental studies, of note, have focused on several cellular components which may eventually become suitable pharmacologic targets for altering chondrocyte apoptosis and/or autophagy in osteoarthritis (**Table 2**). However, the results of these mainly *in vitro* studies point out why it will be necessary to determine the underlying mechanisms regarding how these factors work to inhibit apoptosis. Thus, only after successful evaluation in animal models of RA and OA, can we envision that these targets could eventually be employed in a clinical setting.

was also linked to increasing the levels of Bax, and activated caspase-3/-9 [149].

mechanisms attributed to these molecules have yet to be completely established.

**5.2. Additional potential targets related to apoptosis**

vated PI3K/NF-κB in response to leptin-induced apoptosis.

To summarize this section, gaining a further understanding of how to manipulate specific mIRs to achieve increased or decreased synthesis of specific targets known to influence chondrocyte apoptosis may signal the next major advance in targeted OA and RA therapy designed to promote chondrocyte survival.

### **5. Pharmacologic interventions designed to specifically inhibit chondrocyte apoptosis**

#### **5.1. Signal transduction pathways**

Lewis and Malemud [82] previously reviewed several potential pharmacologic strategies designed to limit the loss of chondrocyte vitality via apoptosis. These included, targeting x-linked inhibitor of apoptosis (XIAP), tumor necrosis factor-like weak inducer of apoptosis (TWEAK), TRAIL, decoy-receptor-3 (DcR3), tumor necrosis factor receptor protein-like molecules, p53 up-regulated modulator of apoptosis (PUMA), and apoptosis-signal-regulating kinases. In that regard, we proposed several interventional strategies which we acknowledged involved developing a deeper understanding of which signal transduction pathways were altered in RA and OA chondrocytes [19, 28, 36, 77, 82, 106]. For example, XIAP, an inhibitor of activated caspase-9, and caspases-3 and -7 [82] was also shown to interact with mitogenactivated protein kinase kinase 2 (MEKK2) [139]. The interaction between XIAP and MEKK2 resulted in a biphasic activation of NF-κB, a known downstream effector of TNF-α-mediated apoptosis. This finding is relevant to the regulation of chondrocyte apoptosis in both RA and OA primarily because XIAP is a well-known inhibitor of apoptosis protein-3 (IAP3) [140]. In fact, we had previously shown that recombinant human TNF-α (rhTNF-α) induced human chondrocyte apoptosis via activation of p38, JNK1/2 and STAT3 [72], whereas apoptosis of the immortalized human chondrocyte line, C-28/I2 induced by rhTNF-α, but not by rhIL-6, was dependent on upstream MEK1/2 [77]. Therefore, we posit that in order to consider using potential drug interventions that alter the activation of various signaling pathways it will be useful to consider what we know about how alterations in receptor-mediated signaling pathways (reviewed in [19]) may influence apoptosis.

Activation of SAPK/MAPK signaling is most often associated with induction of chondrocyte apoptosis. Thus, induction of rabbit articular chondrocyte apoptosis by the nitric oxide (NO) donor sodium nitroprusside (SNP) was linked to inhibition of c-Jun-amino-terminal kinase (JNK) by virtue of the finding that the JNK small molecule inhibitor (SMI) SP600125, reduced the frequency of apoptotic chondrocytes along with NO-induced NF-κB, p53 and caspase-3 [141]. IL-1β, another potent inducer of chondrocyte apoptosis, was also shown to be JNKdependent as both chemical inhibitors of JNK as well as RNA interference with Bim, the latter up-regulated by IL-1β, were shown to be phosphorylated-JNK-dependent [142]. In other studies, chondrocyte apoptosis was again linked to IL-1β-induced activation of p38 kinase [143–145], along with JNK [145], and MMP-3 gene expression with IL-1β negatively regulating chondrocyte autophagy [145]. Of note, AG490, a pan-JAK SMI significantly reduced leptininduced chondrocyte apoptosis *in vitro* as well as reducing STAT3 phosphorylation, reactive oxygen species, MMP-13 and B-cell lymphoma 2-associated X protein [146]. Interestingly, Li et al. [147] showed that the PI3K/NF-κB pathway was activated by TNF-α in human chondrocytes. However, the effect of leptin did not involve mTOR, suggesting that newly developed small molecule mTOR inhibitors (reviewed in [36]) might not be useful for neutralizing activated PI3K/NF-κB in response to leptin-induced apoptosis.

Several attempts to employ various compounds and/or natural products to inhibit chondrocyte apoptosis have taken advantage of various findings related to the role of these compounds and natural products in many of the aforementioned signal transduction pathways. For example, IL-1β-induced chondrocyte apoptosis was inhibited by oligomeric proanthocyanidin, a water-soluble plant polyphenolic compound [148]. Thus, the over-expression of peroxiredoxin 4 (PRDX4), a member of the PRDX family (a molecule essential for scavenging free radicals and reducing reactive oxygen species) reduced IL-1β-induced rat chondrocyte apoptosis [149]. Importantly, AZD5363, an inhibitor of Akt activation also reduced the apoptosis protective effect of PRDX4. In another aspect, chondrocyte apoptosis induced by IL-1β not only involved reduced Bcl-2 levels, activated (i.e., phosphorylated) Akt, and activated PRAS40, a proline-rich 40 kDa Akt substrate and an inhibitor of mTORC1 kinase activity, but was also linked to increasing the levels of Bax, and activated caspase-3/-9 [149].

Shikonin, a compound with anti-tumor, anti-inflammatory, anti-viral and pharmacological efficacy significantly inhibited apoptosis by decreasing IL-1β, TNF-α and inducible NO synthase (iNOS) in rats with experimentally induced OA [150]. The effect of shikonin in this animal model of OA was accompanied not only by reduced caspase-3 and cyclooxygenase-2 activity but also by increased activation of Akt, indicating a prominent role for PI3K/Akt signaling in this rat model of OA. Finally, a few novel targets, including protein kinase R-like endoplasmic reticulum kinase and activating transcription factor 6, were identified as potent regulators of chondrocyte apoptosis *in vitro* and *in vivo* [151], although the precise signaling mechanisms attributed to these molecules have yet to be completely established.

#### **5.2. Additional potential targets related to apoptosis**

Of note, several miRs were identified as potential targets for inducing chondrocyte survival and therefore could be considered anti-apoptosis factors; these included mIR-98 [127–129], mIR-9 [130], mIR-15a-5p [131], mIR-142-3p [132] and mIR-502-5p [133]. Additional mIRs, exemplified by miR-195 [134], mIR-139 [135], mIR-29b-3p [136], mIR-488-3p [137] and mIR-203 [138] could very well be included in this group. For example, by employing the C28/I2 line of immortalized human chondrocytes, Zhao et al. [138] showed that knockdown of mIR-203 targeting the myeloid cell leukemia-1 (MCL-1) protein activated Wnt/β-catenin and JAK/

To summarize this section, gaining a further understanding of how to manipulate specific mIRs to achieve increased or decreased synthesis of specific targets known to influence chondrocyte apoptosis may signal the next major advance in targeted OA and RA therapy designed

Lewis and Malemud [82] previously reviewed several potential pharmacologic strategies designed to limit the loss of chondrocyte vitality via apoptosis. These included, targeting x-linked inhibitor of apoptosis (XIAP), tumor necrosis factor-like weak inducer of apoptosis (TWEAK), TRAIL, decoy-receptor-3 (DcR3), tumor necrosis factor receptor protein-like molecules, p53 up-regulated modulator of apoptosis (PUMA), and apoptosis-signal-regulating kinases. In that regard, we proposed several interventional strategies which we acknowledged involved developing a deeper understanding of which signal transduction pathways were altered in RA and OA chondrocytes [19, 28, 36, 77, 82, 106]. For example, XIAP, an inhibitor of activated caspase-9, and caspases-3 and -7 [82] was also shown to interact with mitogenactivated protein kinase kinase 2 (MEKK2) [139]. The interaction between XIAP and MEKK2 resulted in a biphasic activation of NF-κB, a known downstream effector of TNF-α-mediated apoptosis. This finding is relevant to the regulation of chondrocyte apoptosis in both RA and OA primarily because XIAP is a well-known inhibitor of apoptosis protein-3 (IAP3) [140]. In fact, we had previously shown that recombinant human TNF-α (rhTNF-α) induced human chondrocyte apoptosis via activation of p38, JNK1/2 and STAT3 [72], whereas apoptosis of the immortalized human chondrocyte line, C-28/I2 induced by rhTNF-α, but not by rhIL-6, was dependent on upstream MEK1/2 [77]. Therefore, we posit that in order to consider using potential drug interventions that alter the activation of various signaling pathways it will be useful to consider what we know about how alterations in receptor-mediated signaling path-

Activation of SAPK/MAPK signaling is most often associated with induction of chondrocyte apoptosis. Thus, induction of rabbit articular chondrocyte apoptosis by the nitric oxide (NO) donor sodium nitroprusside (SNP) was linked to inhibition of c-Jun-amino-terminal kinase (JNK) by virtue of the finding that the JNK small molecule inhibitor (SMI) SP600125, reduced

**5. Pharmacologic interventions designed to specifically inhibit**

STAT signaling promoted chondrocyte survival.

ways (reviewed in [19]) may influence apoptosis.

to promote chondrocyte survival.

82 Drug Discovery - Concepts to Market

**chondrocyte apoptosis**

**5.1. Signal transduction pathways**

Several experimental studies, of note, have focused on several cellular components which may eventually become suitable pharmacologic targets for altering chondrocyte apoptosis and/or autophagy in osteoarthritis (**Table 2**). However, the results of these mainly *in vitro* studies point out why it will be necessary to determine the underlying mechanisms regarding how these factors work to inhibit apoptosis. Thus, only after successful evaluation in animal models of RA and OA, can we envision that these targets could eventually be employed in a clinical setting.

is a common pathological finding in RA and OA, cellular mechanisms that result in synovial fibroblast and immune-cell-mediated "apoptosis-resistance," such as those that were found to underlie B-cell activity in RA [168–171], aids in distinguishing between the fundamental underpinning responsible for bony abnormalities in the two conditions. However, equally important is that the increased frequency of apoptotic chondrocytes in both RA and OA constitutes a major contributor to inefficient cartilage repair and synovial joint failure. We contend that any pharmacologic strategies designed to simultaneously target the "apoptosis-resistance" in the RA hyperplastic synovial tissue and the elevated frequency of chondrocyte apoptosis would be an onerous undertaking. So for the present, concentrating on developing agents that suppress or inhibit chondrocyte apoptosis might be the initial way to proceed. For example, the current literature on this subject has already indicated that certain drugs used in the medical therapy of RA suppress chondrocyte apoptosis *in vitro*. In that regard, the drug sulphasalazine, commonly employed in combination with methotrexate, for treating RA [172] was found to inhibit rabbit chondrocyte apoptosis induced by SNP [173]. In this study, the reduced frequency of chondrocyte apoptosis was accompanied by an increase in phosphorylated p38 kinase and

Pharmacologic Interventions for Preventing Chondrocyte Apoptosis in Rheumatoid Arthritis…

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85

ERK1/2 expression compared to treatment of chondrocytes with SNP alone.

actually resulted in an enhancement of cartilage damage in this OA animal model.

lar chondrocyte viability and cartilage integrity.

Another area worthy of consideration is to employ *in vitro* studies to, in effect, rule out for further considerations for developing drugs for treating potential targets of chondrocyte apoptosis. A suitable example of this strategy was a recent finding by Nasi et al. [174] that the NALP3 inflammasome (reviewed in [175]) was not involved in chondrocyte apoptosis characteristic of several alterations in cartilage characteristically found in a murine menisectomy model of OA. Although alterations in the structure of articular cartilage such as cartilage destruction, synovial inflammation, cell death and calcification were seen in this OA animal model, a deficiency in IL-1α had no impact on these features. Importantly, deficiencies in IL-1β and NALP3

The suppression or more favorably the complete inhibition of chondrocyte apoptosis in RA and OA using pharmacologic interventional strategies would be a laudable achievement in the continuing search for novel disease-modifying-anti-rheumatic drugs. A variety of potential novel targets have now been identified during the previous 3 years that at least employing cancer cells induces the frequency of apoptosis. Thus, targets have been identified to induce apoptosis in these cancers and therefore, may be eventually exploited for blocking chondrocyte apoptosis. For example, the activity of 2,5-dihydroxy-3-undecyl-1,4 benzoquinone, 6 g, also known as embelin was reviewed [82] as an inducer of apoptosis in inflammatory breast cancer cells and pancreatic cancer cells. Embelin was also shown to block the transcription of several gene products relevant to tumor cell survival, proliferation, invasiveness and metastatic cancer cell proliferation. Of note, treatment with non-toxic concentrations of embelin could also sensitize cultured malignant glioma to TRAIL-induced apoptosis [176]. Lewis and Malemud [82] reviewed the findings showing that embelin blocked the activation of NF-κB, RANKL and, STAT3, the latter finding demonstrating "proof-of-principle" that STAT3 activated transcription could also be employed to probe the extent to which this signaling pathway was required for maintaining chondrocyte survival *in vitro* [177]. In that regard, these pre-clinical results may provide a suitable platform for exploiting the overall objective of preventing synovial joint failure in RA and OA through the maintenance of normal articu-

1 Hypoxia-inducible factor-1α/-2α.

2 G-protein-coupled receptor kinase interacting protein-1.

3 Insulin-like growth factor-1 binding protein-3.

4 Nerve growth factor 1B.

5 Small glutamine-rich tetratricopeptide repeat-containing β.

6 Heat shock protein-70.

7 Uncoupling protein-4.

8 Reactive oxygen species.

9 Developmental endothelial locus-1.

10RelA/p65 of NF-κB complex.

11Pik3r1 encodes a p85α regulatory protein that is a subunit of phosphatidylinositol 3-kinase (PI3K).

12Beclin-1, a product of the *BECN1* gene is a mammalian ortholog of the yeast autophagy-related gene 6 (Atg6) and BEC-

1 in the *C. elegans* nematode. 13Astragaloside IV.

14Microtubule-associated protein 1A/1B-light chain-I/II.

15P62/sequestosome-1.

16Aquaporin-1.

17Metallothionein-1/metallothionein-2.

18Silent information regulation of transcription 1.

**Table 2.** Cellular factors that regulate chondrocyte apoptosis and/or autophagy *in vitro*.

#### **6. Conclusions and future perspectives**

It is now generally agreed upon by many investigators that a chronic state of inflammation is, in part, responsible for driving and perpetuating the progression of RA (reviewed in [94]) and OA (reviewed in [58, 164]). Moreover, additional recent evidence has indicated that both apoptosis and an altered state of autophagy are critical events in chronic musculoskeletal disorders, such as RA and OA [60, 102–105, 164–167]. Although the loss of chondrocyte vitality is a common pathological finding in RA and OA, cellular mechanisms that result in synovial fibroblast and immune-cell-mediated "apoptosis-resistance," such as those that were found to underlie B-cell activity in RA [168–171], aids in distinguishing between the fundamental underpinning responsible for bony abnormalities in the two conditions. However, equally important is that the increased frequency of apoptotic chondrocytes in both RA and OA constitutes a major contributor to inefficient cartilage repair and synovial joint failure. We contend that any pharmacologic strategies designed to simultaneously target the "apoptosis-resistance" in the RA hyperplastic synovial tissue and the elevated frequency of chondrocyte apoptosis would be an onerous undertaking. So for the present, concentrating on developing agents that suppress or inhibit chondrocyte apoptosis might be the initial way to proceed. For example, the current literature on this subject has already indicated that certain drugs used in the medical therapy of RA suppress chondrocyte apoptosis *in vitro*. In that regard, the drug sulphasalazine, commonly employed in combination with methotrexate, for treating RA [172] was found to inhibit rabbit chondrocyte apoptosis induced by SNP [173]. In this study, the reduced frequency of chondrocyte apoptosis was accompanied by an increase in phosphorylated p38 kinase and ERK1/2 expression compared to treatment of chondrocytes with SNP alone.

Another area worthy of consideration is to employ *in vitro* studies to, in effect, rule out for further considerations for developing drugs for treating potential targets of chondrocyte apoptosis. A suitable example of this strategy was a recent finding by Nasi et al. [174] that the NALP3 inflammasome (reviewed in [175]) was not involved in chondrocyte apoptosis characteristic of several alterations in cartilage characteristically found in a murine menisectomy model of OA. Although alterations in the structure of articular cartilage such as cartilage destruction, synovial inflammation, cell death and calcification were seen in this OA animal model, a deficiency in IL-1α had no impact on these features. Importantly, deficiencies in IL-1β and NALP3 actually resulted in an enhancement of cartilage damage in this OA animal model.

The suppression or more favorably the complete inhibition of chondrocyte apoptosis in RA and OA using pharmacologic interventional strategies would be a laudable achievement in the continuing search for novel disease-modifying-anti-rheumatic drugs. A variety of potential novel targets have now been identified during the previous 3 years that at least employing cancer cells induces the frequency of apoptosis. Thus, targets have been identified to induce apoptosis in these cancers and therefore, may be eventually exploited for blocking chondrocyte apoptosis. For example, the activity of 2,5-dihydroxy-3-undecyl-1,4 benzoquinone, 6 g, also known as embelin was reviewed [82] as an inducer of apoptosis in inflammatory breast cancer cells and pancreatic cancer cells. Embelin was also shown to block the transcription of several gene products relevant to tumor cell survival, proliferation, invasiveness and metastatic cancer cell proliferation. Of note, treatment with non-toxic concentrations of embelin could also sensitize cultured malignant glioma to TRAIL-induced apoptosis [176]. Lewis and Malemud [82] reviewed the findings showing that embelin blocked the activation of NF-κB, RANKL and, STAT3, the latter finding demonstrating "proof-of-principle" that STAT3 activated transcription could also be employed to probe the extent to which this signaling pathway was required for maintaining chondrocyte survival *in vitro* [177]. In that regard, these pre-clinical results may provide a suitable platform for exploiting the overall objective of preventing synovial joint failure in RA and OA through the maintenance of normal articular chondrocyte viability and cartilage integrity.

**6. Conclusions and future perspectives**

1

2

3

4

5

6

7

8

9

Hypoxia-inducible factor-1α/-2α.

84 Drug Discovery - Concepts to Market

Nerve growth factor 1B.

Heat shock protein-70.

Uncoupling protein-4.

Reactive oxygen species.

1 in the *C. elegans* nematode. 13Astragaloside IV.

15P62/sequestosome-1. 16Aquaporin-1.

Developmental endothelial locus-1. 10RelA/p65 of NF-κB complex.

17Metallothionein-1/metallothionein-2.

18Silent information regulation of transcription 1.

G-protein-coupled receptor kinase interacting protein-1.

Small glutamine-rich tetratricopeptide repeat-containing β.

14Microtubule-associated protein 1A/1B-light chain-I/II.

Insulin-like growth factor-1 binding protein-3.

It is now generally agreed upon by many investigators that a chronic state of inflammation is, in part, responsible for driving and perpetuating the progression of RA (reviewed in [94]) and OA (reviewed in [58, 164]). Moreover, additional recent evidence has indicated that both apoptosis and an altered state of autophagy are critical events in chronic musculoskeletal disorders, such as RA and OA [60, 102–105, 164–167]. Although the loss of chondrocyte vitality

11Pik3r1 encodes a p85α regulatory protein that is a subunit of phosphatidylinositol 3-kinase (PI3K).

**Table 2.** Cellular factors that regulate chondrocyte apoptosis and/or autophagy *in vitro*.

12Beclin-1, a product of the *BECN1* gene is a mammalian ortholog of the yeast autophagy-related gene 6 (Atg6) and BEC-

**Factor Target Reference** HIF-1α/HIF-2α1 HIF-1α—SOX9; HIF-2α—Fas [152] Integrin-β1 G1T12 [153] IGFBP-33 Nur774 [154] SGBT5 Caspase-3/Hsp706 [155] UCP47 ROS8 [156] DEL19 Caspase-3/Caspase-7 [157] Rela10 Pik3r111 [158] Beclin12 Bcl-2; Bcl-2 associated X [159] AST13 LC3-II/I14; P62/SQSTM115 [160] AQP-116 Caspase-3 [161] Mt1/Mt217 ROS8 [162] Sirt118 Bcl-2; Bax [163]

#### **Acknowledgements**

The results of experimental studies cited in Refs. [70, 72, 77, 80] were supported in part by grants from the National Institutes of Health, Takeda Pharmaceuticals of North America and Genentech/Roche Group.

[10] Beug ST, Cheung HH, LaCasse EC, et al. Modulation of immune signaling by inhibitors of apoptosis. Trends in Immunology. 2012;**33**:535-545. DOI: 10.1016/j.it.2012.06.004 [11] Liu H, Pope RM. Apoptosis in rheumatoid arthritis: Friend or foe. Rheumatic Disease

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#### **Author details**

Charles J. Malemud

Address all correspondence to<EMAIL_ADDRESS>
Department of Medicine, Division of Rheumatic Diseases, Case Western Reserve University School of Medicine/University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA

#### **References**

[10] Beug ST, Cheung HH, LaCasse EC, et al. Modulation of immune signaling by inhibitors of apoptosis. Trends in Immunology. 2012;**33**:535-545. DOI: 10.1016/j.it.2012.06.004

**Acknowledgements**

86 Drug Discovery - Concepts to Market

Genentech/Roche Group.

**Author details**

Charles J. Malemud

**References**

Address all correspondence to<EMAIL_ADDRESS>
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The results of experimental studies cited in Refs. [70, 72, 77, 80] were supported in part by grants from the National Institutes of Health, Takeda Pharmaceuticals of North America and

Department of Medicine, Division of Rheumatic Diseases, Case Western Reserve University School of Medicine/University Hospitals Cleveland Medical Center, Cleveland, Ohio, USA

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**Chapter 5**

**Provisional chapter**

**Medicinal Plants of West Godavari**

**Medicinal Plants of West Godavari**

DOI: 10.5772/intechopen.73499

Medicinal plants are one of the nature's greatest gifts to the mankind. Each plant will have an exquisite deal of character, which can act as an antidote to various of diseases. Traditional medicine has become a vital alternative source of medicine all over the world today with some approximation of about 80% of the primary health care system in some developing countries. Medicinal plants are known to comprise of hundreds of active constituents that may be potentially useful for the development of therapeutic agents. The development of therapeutic agents involves the isolation and identification of bioactive compounds from plant materials which is crucial for drug discovery. Researchers from all around the globe have focused on drug discovery from the natures' wonder medicinal plants, forming an important group of complementary and alternative medicine (CAM) therapy. West Godavari is a part of Andhra Pradesh, India, which hosts several plants that have high therapeutic significance. Each of the plants has a unique feature which can be employed for healing of various lethal diseases. The present examination intends to review the therapeutic plant assets of West Godavari area Andhra Pradesh. This evaluation also offers the critical elements which include medicinal properties of various medicinal plants found in West Godavari district of

**Keywords:** drug discovery, traditional medicine, West Godavari district, nature,

The great thing that nature has given us is the medicinal plants. Each plant will have a great

deal of character, which can act as an antidote against different types of diseases.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

Sudhakar Pola and Venkata Narasimha Kadali

Sudhakar Pola and Venkata Narasimha Kadali

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.73499

Andhra Pradesh, India.

antidote

**1. Introduction**

**Abstract**

#### **Medicinal Plants of West Godavari Medicinal Plants of West Godavari**

Sudhakar Pola and Venkata Narasimha Kadali Sudhakar Pola and Venkata Narasimha Kadali

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.73499

#### **Abstract**

Medicinal plants are one of the nature's greatest gifts to the mankind. Each plant will have an exquisite deal of character, which can act as an antidote to various of diseases. Traditional medicine has become a vital alternative source of medicine all over the world today with some approximation of about 80% of the primary health care system in some developing countries. Medicinal plants are known to comprise of hundreds of active constituents that may be potentially useful for the development of therapeutic agents. The development of therapeutic agents involves the isolation and identification of bioactive compounds from plant materials which is crucial for drug discovery. Researchers from all around the globe have focused on drug discovery from the natures' wonder medicinal plants, forming an important group of complementary and alternative medicine (CAM) therapy. West Godavari is a part of Andhra Pradesh, India, which hosts several plants that have high therapeutic significance. Each of the plants has a unique feature which can be employed for healing of various lethal diseases. The present examination intends to review the therapeutic plant assets of West Godavari area Andhra Pradesh. This evaluation also offers the critical elements which include medicinal properties of various medicinal plants found in West Godavari district of Andhra Pradesh, India.

DOI: 10.5772/intechopen.73499

**Keywords:** drug discovery, traditional medicine, West Godavari district, nature, antidote

#### **1. Introduction**

The great thing that nature has given us is the medicinal plants. Each plant will have a great deal of character, which can act as an antidote against different types of diseases.

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2018 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Traditional medicine has become a vital alternative source of medicine all over the world today with some approximation of about 80% of the primary health care system in some developing countries (e.g., Nigeria, Ghana, China, and India [1, 2]).

It has turned out to be fundamental, subsequently, to outfit the overall population incorporating human services experts with adequate data to encourage better comprehension of the dangers related to the utilization of these items and to guarantee that all solutions are protected and of reasonable quality. Discussion in this review is restricted to lethality-related issues, and significant well-being concerns are emerging from the utilization of homegrown drugs and additional factors advancing them. Some essential difficulties related to the successful checking of security of these homegrown cures are additionally featured to refocusing appropriate administrative offices on the requirement for viability and guaranteeing suffi-

Medicinal Plants of West Godavari

103

http://dx.doi.org/10.5772/intechopen.73499

The worldwide acknowledgment and utilization of natural medicines and related items keep on assuming exponential increment. Issues identifying with unfavorable responses as of late are additionally ending up more distinctive, expanding in common and no longer accessible to refute as a result of prior misguided judgment with regards to or classifying homegrown restorative items as "protected" because they are getting from "characteristic" source. In this manner, regulatory approaches on homegrown pharmaceuticals should be institutionalized and reinforced on a worldwide scale. Pertinent administrative experts in various nations of the world should be proactive and keep on putting proper set up measures to secure the general well-being by guaranteeing that every single natural prescription endorsed available to be purchased sheltered and of reasonable quality. Suppliers of pharmaceuticals, for example, doctors, attendants, and drug specialists, regularly have little preparing in and comprehension of how homegrown solutions influence the well-being of their patients. Satisfactory preparation is present extremely basic since most patients are regularly on different sorts of the solution or non-professionally prescribed drugs. Additionally, it is vital that all suppliers of natural solutions are adequately enabled to assume a part in observing well-being of homegrown prescriptions. This, be that as it may, ought to be in a joint effort with the traditional healers. For this to be successful, it is basic to make a climate of trust to encourage satisfactory sharing of information about the utilization and well-being of homegrown solutions. Truth be told to suppliers of homegrown solutions, and patients/shoppers are imperative for the version of possibly genuine dangers from misuse of natural medications. The supplier must demonstrate adequate responsibility toward understanding the utilization of homegrown drugs.

West Godavari is a part of Andhra Pradesh, India, which hosts several plants that have high medicinal importance. Each of the plants has a unique feature which can heal lethal diseases. Some researchers have drawn some plants into attention from lots of surveys. It also hosts

The traditional plant healing has brought a significant breakthrough in curing diseases very efficiently. The nutraceutical companies have isolated plant compounds based on the knowledge provided by the traditional healers. An adequate amount of knowledge is still to be known from the traditional healers. There is a substantial increase in the use of Ayurvedic medicines and medicines derived from plant sources. The reason being its efficacy and lack of side effects, and there is an economic point of view as well. Based on the information given by the traditional healing system, several modern scientific studies are being conducted on the various medicinal plants.

Some of the medicinal plants have been perished because of urbanization. The ancient knowledge about medicinal plants had not been documented, and many of the valuable plants are

traditional healers who can efficiently cure some of the deadly diseases.

cient assurance of general well-being and advancing well-being.

India has a recognized traditional system of medicine, that is, Ayurveda, Siddha, Unani, Homeopathy, Yoga, and Naturopathy which placed India in a unique position in the world [3].

As the growth of knowledge has increased, the number of new plant-derived drugs grow at an accelerated pace. India has an enormous wealth of medicinal plants, and often it has been referred to as the Medicinal Garden of the world [4].

Medicinal plants are known to comprise hundreds of active constituents that may be potentially useful for the development of therapeutic agents. The development of therapeutic agents involves Identification and segregation of bioactive compounds from plant materials that are crucial for drug discovery [5].

Researchers from all around the globe have focused on drug discovery from the nature's wonder medicinal plants, an important group of complementary and alternative medicine (CAM) therapy [5].

The man has acclimated himself with plants and utilized them in an assortment of courses all through the ages. Primitive man looking for nourishment and to adapt efficiently to human sufferings started to recognize those plants appropriate for restorative reason from others with complete pharmacological activity. This connection between plants and man has developed, and many plants came to be utilized as medicines. The development of information to cure infections proceeded at a quick pace and various new plant-derived drugs expanded in this manner.

Herbs employed in ancient medicines represent a tiny, low portion of present plants solely. With the advances in informative innovation and science, many bioactive concoction substances are distinguished in plants or foodstuffs through phytochemical and pharmacological studies.

The clinical utilization of plants portrayed in Indian Vedas for curing distinctive maladies. In the present setting, the conventional arrangement of pharmaceutical is broadly acknowledged and drilled by individuals around the world.

The natural solution is drilled around the world. For a considerable length of time, individuals have swung to natural solutions for basic cure illnesses, for example, colds, sensitivity, annoy stomachs, and toothaches, and the pattern is continually expanding. In this way, there has been a move in general pattern from manufactured to homegrown solutions.

The advancement of plant-derived drugs began when improvement of science. The homegrown drug is compelling, minor symptom, and moderate than the medications purchased from an allopathic pharmaceutical. Homegrown medications incorporate herbs, homegrown materials, natural arrangements, and homegrown items that contain diverse parts of plants or other plant materials as dynamic fixings.

As the worldwide utilization of homegrown therapeutic items keeps on developing and numerous, the newest items are brought into the market, general medical problems and concerns encompassing their well-being are likewise progressively perceived. Although some homegrown herbs have promising potential and are utilized, a considerable lot of them stay untested and their utilization likewise not observed.

It has turned out to be fundamental, subsequently, to outfit the overall population incorporating human services experts with adequate data to encourage better comprehension of the dangers related to the utilization of these items and to guarantee that all solutions are protected and of reasonable quality. Discussion in this review is restricted to lethality-related issues, and significant well-being concerns are emerging from the utilization of homegrown drugs and additional factors advancing them. Some essential difficulties related to the successful checking of security of these homegrown cures are additionally featured to refocusing appropriate administrative offices on the requirement for viability and guaranteeing sufficient assurance of general well-being and advancing well-being.

Traditional medicine has become a vital alternative source of medicine all over the world today with some approximation of about 80% of the primary health care system in some

India has a recognized traditional system of medicine, that is, Ayurveda, Siddha, Unani, Homeopathy, Yoga, and Naturopathy which placed India in a unique position in the world [3]. As the growth of knowledge has increased, the number of new plant-derived drugs grow at an accelerated pace. India has an enormous wealth of medicinal plants, and often it has been

Medicinal plants are known to comprise hundreds of active constituents that may be potentially useful for the development of therapeutic agents. The development of therapeutic agents involves Identification and segregation of bioactive compounds from plant materials

Researchers from all around the globe have focused on drug discovery from the nature's wonder medicinal plants, an important group of complementary and alternative medicine

The man has acclimated himself with plants and utilized them in an assortment of courses all through the ages. Primitive man looking for nourishment and to adapt efficiently to human sufferings started to recognize those plants appropriate for restorative reason from others with complete pharmacological activity. This connection between plants and man has developed, and many plants came to be utilized as medicines. The development of information to cure infections proceeded at a quick pace and various new plant-derived drugs expanded in this manner.

Herbs employed in ancient medicines represent a tiny, low portion of present plants solely. With the advances in informative innovation and science, many bioactive concoction substances are distinguished in plants or foodstuffs through phytochemical and pharmacological studies. The clinical utilization of plants portrayed in Indian Vedas for curing distinctive maladies. In the present setting, the conventional arrangement of pharmaceutical is broadly acknowl-

The natural solution is drilled around the world. For a considerable length of time, individuals have swung to natural solutions for basic cure illnesses, for example, colds, sensitivity, annoy stomachs, and toothaches, and the pattern is continually expanding. In this way, there

The advancement of plant-derived drugs began when improvement of science. The homegrown drug is compelling, minor symptom, and moderate than the medications purchased from an allopathic pharmaceutical. Homegrown medications incorporate herbs, homegrown materials, natural arrangements, and homegrown items that contain diverse parts of plants or

As the worldwide utilization of homegrown therapeutic items keeps on developing and numerous, the newest items are brought into the market, general medical problems and concerns encompassing their well-being are likewise progressively perceived. Although some homegrown herbs have promising potential and are utilized, a considerable lot of them stay

has been a move in general pattern from manufactured to homegrown solutions.

developing countries (e.g., Nigeria, Ghana, China, and India [1, 2]).

referred to as the Medicinal Garden of the world [4].

edged and drilled by individuals around the world.

other plant materials as dynamic fixings.

untested and their utilization likewise not observed.

that are crucial for drug discovery [5].

(CAM) therapy [5].

102 Drug Discovery - Concepts to Market

The worldwide acknowledgment and utilization of natural medicines and related items keep on assuming exponential increment. Issues identifying with unfavorable responses as of late are additionally ending up more distinctive, expanding in common and no longer accessible to refute as a result of prior misguided judgment with regards to or classifying homegrown restorative items as "protected" because they are getting from "characteristic" source. In this manner, regulatory approaches on homegrown pharmaceuticals should be institutionalized and reinforced on a worldwide scale. Pertinent administrative experts in various nations of the world should be proactive and keep on putting proper set up measures to secure the general well-being by guaranteeing that every single natural prescription endorsed available to be purchased sheltered and of reasonable quality. Suppliers of pharmaceuticals, for example, doctors, attendants, and drug specialists, regularly have little preparing in and comprehension of how homegrown solutions influence the well-being of their patients. Satisfactory preparation is present extremely basic since most patients are regularly on different sorts of the solution or non-professionally prescribed drugs. Additionally, it is vital that all suppliers of natural solutions are adequately enabled to assume a part in observing well-being of homegrown prescriptions. This, be that as it may, ought to be in a joint effort with the traditional healers. For this to be successful, it is basic to make a climate of trust to encourage satisfactory sharing of information about the utilization and well-being of homegrown solutions. Truth be told to suppliers of homegrown solutions, and patients/shoppers are imperative for the version of possibly genuine dangers from misuse of natural medications. The supplier must demonstrate adequate responsibility toward understanding the utilization of homegrown drugs.

West Godavari is a part of Andhra Pradesh, India, which hosts several plants that have high medicinal importance. Each of the plants has a unique feature which can heal lethal diseases. Some researchers have drawn some plants into attention from lots of surveys. It also hosts traditional healers who can efficiently cure some of the deadly diseases.

The traditional plant healing has brought a significant breakthrough in curing diseases very efficiently. The nutraceutical companies have isolated plant compounds based on the knowledge provided by the traditional healers. An adequate amount of knowledge is still to be known from the traditional healers. There is a substantial increase in the use of Ayurvedic medicines and medicines derived from plant sources. The reason being its efficacy and lack of side effects, and there is an economic point of view as well. Based on the information given by the traditional healing system, several modern scientific studies are being conducted on the various medicinal plants.

Some of the medicinal plants have been perished because of urbanization. The ancient knowledge about medicinal plants had not been documented, and many of the valuable plants are at the edge of extinction. The government and NGO should take necessary conservatory steps to avoid extinction of valuable medicinal plants.

**2.2.** *Abutilon indicum*

and jaundice [16].

**2.3.** *Abrus precatorius*

modic activity [36].

measuring gold and silver [28].

*2.3.1. Scientific studies on Abrus precatorius*

*2.2.1. Scientific studies on Abutilon indicum*

[26], and hepatoprotective activity [27].

leprosy [17].

*Abutilon indicum* (Linn.) belong to family Malvaceae and it is scattered throughout Andhra Pradesh, India, and it is being used for treating various diseases like diabetes, leprosy, ulcer,

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In Siddha System of Medicine, it has been using as a remedy for jaundice, piles, ulcers, and

This plant is proved to have diuretic activity [18], antimycotic activity [19], anti-arthritic activity [20], anti-inflammatory and anti-asthmatic activity [21], hypoglycemic activity [22], anticonvulsant activity [23], wound healing activity [24], antidiarrhoeal activity [25], antimalarial

*Abrus precatorius* belongs to family Fabaceae. *Abras precatorius* is a plant originating from Southeast Asia. The name *Abrus*, means beautiful or graceful, is used to describe the appearance of the seed [28]. The seeds of *Abrus precatorius* have a history in a variety of roles because they have uniform size and weight. They were once called as Rati, and utilized as weights for

This plant is demonstrated to have antibacterial activity [29], diuretic activity [30], nephroprotective activity [31], neuroprotective activity [32], bronchodilator activity [33], effect on neuromuscular antioxidant activity [34], anticonvulsant activity [35], antispas-

Several bioactive compounds isolated from medicinal plants are in excess demand in nutraceutical companies.

The present study aims to review the medicinal plant resources of West Godavari district, Andhra Pradesh. This review also deals with the critical aspects such as medicinal properties of various medicinal plants present in West Godavari district of Andhra Pradesh, India. This article deals with the medicinal properties of plants which are implicated in various diseases such as jaundice, cardiac diseases, asthma, cancer, skin diseases, diarrhea, conjunctivitis, ulcers, diabetes, leprosy, syphilis, and neural diseases.

This article also deals with the scientific studies conducted by the researchers on numerous medicinal plants present in West Godavari.

### **2. Medicinal plants of West Godavari**

#### **2.1.** *Annona reticulata* **L.**

*Annona* genus (Annonaceae) has about 119 species [6]. *Annona reticulata* belongs to the plant family Annonaceae and is a semi-evergreen and small deciduous tree [7]. *Annona* species are having a place in custard apple family and is cultivated everywhere in India for its fruit. All components of genus *Annona* are employed in natural medication within the tropics. It is thought to be a smart supply of natural antioxidants for various diseases.

It is being cultivated in Peru and Brazil and is grown mostly in the Bahamas and occasionally in southern Florida, Bermuda, the east coast of Malaysia, and throughout Southeast Asia and the Philippines [8, 9].

#### *2.1.1. Scientific evidences*

This plant is known to possess antioxidant activity [7], anticancer activity [10–13], antihelminthic activity [14], anti-inflammatory activity [6], analgesic, and CNS depressant activity [15].

#### **2.2.** *Abutilon indicum*

at the edge of extinction. The government and NGO should take necessary conservatory steps

Several bioactive compounds isolated from medicinal plants are in excess demand in nutra-

The present study aims to review the medicinal plant resources of West Godavari district, Andhra Pradesh. This review also deals with the critical aspects such as medicinal properties of various medicinal plants present in West Godavari district of Andhra Pradesh, India. This article deals with the medicinal properties of plants which are implicated in various diseases such as jaundice, cardiac diseases, asthma, cancer, skin diseases, diarrhea, conjunctivitis,