Cathepsin K+ Non-Osteoclast Cells in the Skeletal System: Function, Models, Identity, and Therapeutic Implications

Abstract

Cathepsin K (Ctsk) is a cysteine protease of the papain superfamily initially identified in differentiated osteoclasts; it plays a critical role in degrading the bone matrix. However, subsequent in vivo and in vitro studies based on animal models elucidate novel subpopulations of Ctsk-expressing cells, which display markers and properties of mesenchymal stem/progenitor cells. This review introduces the function, identity, and role of Ctsk+ cells and their therapeutic implications in related preclinical osseous disorder models. It also summarizes the available in vivo models for studying Ctsk+ cells and their progeny. Further investigations of detailed properties and mechanisms of Ctsk+ cells in transgenic models are required to guide potential therapeutic targets in multiple diseases in the future.

Mechanosensitive protein polycystin-1 promotes periosteal stem/progenitor cells osteochondral differentiation in fracture healing

“…Nevertheless, due to the absence of specific markers to distinguish PSPCs in vivo , which PSPCs recognize fracture and how they initiate the repair process remain unknown. Ctsk , a specific biomarker of subsets of stem/progenitor cells, helps determine the crucial cells involved in skeletal diseases 22 , 49 . Here, we identified PSPCs carrying the Ctsk gene at the apex of the differentiation hierarchy.…”

“…Genetic mouse models and lineage tracing techniques have identified several markers that label the PSPCs during bone fracture healing, including cathepsin K ( Ctsk ), PDGFRα , and Prrx1 8 - 10 , 17 - 21 . Recently, Ctsk -positive cells have been reported to be a primary source of PSPCs for cortical bone homeostasis and regeneration with the intramembranous and endochondral bone formation ability 10 , 22 . However, crucial questions remain about which type of PSPCs sense mechanical signals in the fracture callus microenvironment and how they convert mechanical signals into biological signals.…”

Age-related secretion of grancalcin by macrophages induces skeletal stem/progenitor cell senescence during fracture healing

“…In this study, we selected Ctsk as a marker of SSPCs to investigate the role of callus SSPCs in vivo, which is consistent with a previous study showing that periosteal SSPCs express Ctsk. 31 , 56 Ctsk was initially identified in mature osteoclasts. To exclude the possible effects of Plxnb2 deletion in osteoclasts on fracture repair, we used another mouse model with depletion of Plxnb2 in Prrx1 + SSPCs to confirm the critical effects of Plxnb2 in SSPCs.…”

Evaluating osteogenic effects associated with the incorporation of ascorbic acid in mineralized collagen scaffolds

“…65,66 Mouse models lacking OPN expression display minimal impact on bone formation but notable inhibitory effects on osteoclast differentiation and bone resorption. 67,68 CTSK is another well-established osteoclast marker, known to be heavily involved with bone resorption, 69,70 and the presence of ascorbic acid has been shown to reduce CTSK mRNA expression. 62,71 While our results did not indicate a reduction across all timepoints, our observation of delayed CTSK expression with greater ascorbic acid concentration remains in broad agreement with the work of others, indicating a possible reduction in osteoclastic activity with ascorbic acid incorporation.…”