Transforming growth factor beta (TGF-β) is a key factor mediating the intercellular crosstalk between the hematopoietic stem cells and their microenvironment. Here, we investigated the skeletal phenotype of transgenic mice expressing constitutively active TGF-β receptor type I under the control of Mx1-Cre (Mx1;TβRICAmice). μCT analysis showed decreased cortical thickness, and cancellous bone volume in both femurs and mandibles. Histomorphometric analysis confirmed a decrease in cancellous bone volume due to increased osteoclast number and decreased osteoblast number. Primary osteoblasts showed decreased ALP and mineralization. ConstitutiveTβRIactivation increased osteoclast differentiation. qPCR analysis showed thatTnfsf11/Tnfrsf11bratio,Ctsk,Sufu, andCsf1were increased whereasRunx2,Ptch1, and Ptch2were decreased inMx1;TβRICAfemurs. Interestingly,Gli1, Wnt3a,Sp7, Alpl, Ptch1, Ptch2, andShhmRNA expression were reduced whereasTnfsf11/Tnfrsf11bratio was increased inMx1;TβRICAmandibles. Similarly, osteoclast-related genes were increased inMx1;TβRICAosteoclasts whereas osteoblast-related genes were reduced inMx1;TβRICAosteoblasts. Western blot analysis indicated that SMAD2 and SMAD3 phosphorylation was increased inMx1;TβRICAosteoblasts, and SMAD3 phosphorylation was increased inMx1;TβRICAosteoclasts. CTSK was increased while RUNX2 and PTCH1 was decreased inMx1;TβRICAmice. Microindentation analysis indicated decreased hardness inMx1;TβRICAmice. Our study indicated thatMx1;TβRICAmice were osteopenic by increasing osteoclast number and decreasing osteoblast number, possibly by suppressing Hedgehog signaling pathways.