1. Introduction
bone disease, Ochronosis, alkaptonuria, autosomal recessive disorder, PRO-C1, Alkaptonuria, connective tissue damage, ochronosis
BONE DISEASE, OCHRONOSIS, ALKAPTONURIA, RARE DISEASE, HYPERPIGMENTATION, ALKAPTONURIA, DISEASE, DEFICIENCY OF HOMOGENTISATE 1,2-DIOXYGENASE, OCHRONOSIS, PATHOGENESIS
Nitisinone has been approved for treatment of alkaptonuria (AKU). Non-invasive biomarkers of joint tissue remodelling could aid in understanding the molecular changes in AKU pathogenesis and how these can be affected by treatment. Serological and urinary biomarkers of type I collagen and II collagen in AKU were investigated in patients enrolled in the randomized SONIA 2 (NCT01916382) clinical study at baseline and yearly until the end of the study (Year 4). The trajectories of the biomarkers over time were observed. After treatment with nitisinone, the biomarkers of type I collagen remodelling increased at Year 1 (19% and 40% increase in CTX-I and PRO-C1, respectively), which was potentially reflected in the higher degree of mobility seen following treatment. The biomarkers of type II collagen remodelling decreased over time in the nitisinone group: C2M showed a 9.7% decline at Year 1, and levels then remained stable over the following visits; CTX-II showed a 26% decline at Year 3 and 4 in the nitisinone-treated patients. Nitisinone treatment induced changes in biomarkers of bone and cartilage remodelling. These biomarkers can aid patient management and deepen our knowledge of the molecular mechanisms of this rare disease.Alkaptonuria (AKU), also known as black bone disease due to its manifestation of hyperpigmentation, is a rare autosomal recessive disorder caused by the deficiency of homogentisate 1,2-dioxygenase (HGD), which causes an accumulation of homogentisic acid (HGA), some of which is deposited as ochronotic pigment in connective tissues, particularly weight-bearing cartilages [After the clinical studies, Suitability of Nitisinone in Alkaptonuria 1 (SONIA 1) [In AKU mice, nitisinone is completely effective in preventing ochronosis if administered from birth [Non-invasive biomarkers of connective tissue damage in AKU would be helpful in detecting the earliest sign of the disease taking hold. The SOFIA (Subclinical Ochronosis Features in Alkaptonuria) study concluded that ochronosis can be present before 20 years of age [Non-invasive biomarkers of extracellular matrix (ECM) remodelling were previously tested in serum and urine of 40 patients enrolled in the 4-week international, multicentre, randomised, open-label, no-treatment controlled, parallel-group, dose-response SONIA 1 study [In the current study, the above biomarkers were tested in the larger population of SONIA 2 to observe whether the treatment with nitisinone altered the dynamics of cartilage and bone remodelling and whether the changes were related to the severity of the disease.