Articular cartilage protection in Ctsk^‐/‐ mice is associated with cellular and molecular changes in subchondral bone and cartilage matrix

Abstract

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.

Subchondral Bone Remodeling: A Therapeutic Target for Osteoarthritis

“…One of the key enzymes expressed by osteoclasts for bone resorption is cathepsin K (CTSK). Ctsk knockout mice (Ctsk −/− ) maintained cartilage volume and structure in OA surgical model of destabilization of the medial meniscus (DMM model), although the TRAP + osteoclast population in subchondral bone was increased in both wild type and Ctsk −/− mice (Soki et al, 2018), and the subchondral bone was also preserved in OA Ctsk −/− mice (Soki et al, 2018).…”

Hyaluronan suppresses enhanced cathepsin K expression via activation of NF-κB with mechanical stress loading in a human chondrocytic HCS-2/8 cells

“…Previous studies have reported an increased expression of cathepsin K in human OA cartilage and chondrocytes, as compared to healthy cartilage and chondrocytes 13 . They also demonstrated that OA progression was delayed in cathepsin K knockout mice using a surgical OA model 17,18 . Several other studies have reported that inhibition of cathepsin K resulted in reduced cartilage degeneration and inflammation in mouse OA models and collagen-induced arthritis [19][20][21] .…”

Bioinformatics approach for potential genes associated with osteoarthritis

“…And this is similar to our findings. Additionally, experimental studies have confirmed that CTSK −/− mice exhibit a reduction in the remodeling of subchondral bone and calcified cartilage in the destabilization of the medial meniscus induced OA [38]. TIMP1 belongs to TIMP gene family, which encodes a protein that is a natural inhibitor of matrix metalloproteinase (MMP) involved in the pathology of OA [39].…”