--- - |2+ Osteoarthritis (OA) is a degenerative disease and a major cause of chronic disability in aging individuals. Cathepsin K (CatK), encoded by the Ctsk gene, has been implicated in the pathogenesis of pycnodysostosis and osteoporosis. The use of a selective inhibitor of CatK was recently shown to delay OA progression in rabbits. However, the cellular mechanisms underlying these protective effects remain unexplored. We examined articular cartilage maintenance and joint bone remodeling using Ctsk null mice (Ctsk‐/‐) which underwent destabilization of the medial meniscus (DMM). We found that Ctsk‐/‐ mice displayed delayed remodeling of subchondral and calcified cartilage by osteoclasts and chodroclasts respectively in DMM‐induced osteoarthritis. While WT mice displayed a more severe OA phenotype than Ctsk‐/‐ mice at 16 weeks, higher subchondral bone volume and lower trabecular spacing were also observed in surgically‐induced OA joints of Ctsk‐/‐ mice. However, no differences were seen in non‐surgical controls. During OA progression, TRAP+ osteoclast numbers were increased in both WT and Ctsk‐/‐ mice. However, Ctsk‐/‐ mice had fewer physis‐derived chondroclasts than WT when OA was present. These data suggest that CatK may differentially regulate chondroclastogenesis in the growth plate. Targeted PCR arrays of RNA harvested from laser captured osteoclasts in the subchondral bone and chondroclasts in the growth plate demonstrated differential expression of Atp6v0d2, Tnfrsf11a, Ca2, Calcr, Ccr1, Gpr68, Itgb3, Nfatc1, and Syk genes between WT and Ctsk‐/‐ mice at 8‐ and 16‐weeks post‐DMM. Our data provide insight into the cellular mechanisms by which cathepsin K deletion delays OA progression in mice. - Journal of Cellular Physiology, Volume 233, Issue 11, Page 8666-8676, November 2018.