TGF-βs have essential roles in coupling bone construction by osteoblast and bone destruction by osteoclast7,8 through osteoclast-mediated Atp6i-specific extracellular acidification9,10 and Cathepsin K-specific extracellular matrix proteins.11,12 Multiple BMPs are also potent osteogenic agents that possess significant clinical implication to accelerate fracture healing in patients.13,14 Furthermore, TGF-βs and BMPs regulate postnatal joint cartilage homeostasis, thus dysregulated TGF-β and BMP signaling are often associated with osteoarthritis in both human disease and mouse models.15–19. This evidence concerns the gene CLN5 and osteoarthritis.