Abstract
Selective inhibition of Cathepsin K (CatK) has a promising therapeutic potential for diseases associated with bone loss and osseous inflammation, such as osteoarthritis, periodontitis, and osteoporosis. In horses, stress-related bone injuries are common and accompanied by bone pain and inflammation resulting in excessive bone resorption and periostitis. VEL-0230 is a highly selective inhibitor of CatK that significantly decreased bone resorption and increased bone formation biomarkers. The goal of this study was to demonstrate the presence of CatK in equine bone and a simultaneous influence on the bone marrow cellular components including function and differentiation. Our objectives were: 1) to investigate the tissue localization of CatK protein in equine bone using immunohistochemistry, and 2) to determine the effect of CatK inhibition on osteoclastogenic, chondrogenic and osteogenic differentiation potential of equine stem and progenitor cells in vitro using histochemical staining and differentiation-related gene expression analyses. Bone biopsies, harvested from the tuber coxae and proximal phalanx of six healthy horses, were processed for immunostaining against CatK. Sternal bone marrow aspirates were cultured in 0, 1, 10, or 100 μM of VEL-0230 and subsequent staining scoring and gene expression analyses performed. All cells morphologically characterized as osteoclasts and moderate number of active bone lining osteoblasts stained positive for CatK. Histochemical staining and gene expression analyses revealed a significant increase in the osteoclastogenic, chondrogenic and osteogenic differentiation potential of equine bone marrow cells, which was VEL-0230-concentration dependent for the latter two. These results suggested that CatK inhibition may have anabolic effects on bone and cartilage regeneration that may be explained as a feedback response to CatK depletion. In conclusion, the use of CatK inhibition to reduce inflammation and associated bone resorption in equine osseous disorders may offer advantages to other therapeutics that would require further study.
Highlights
Cathepsin K (CatK) has become a major therapeutic target for the treatment of bone loss from osteoporosis[1], with potential for use in other diseases associated with bone resorption
All morphologically characterized osteoclasts stained positive for CatK in both Tuber coxae (TC) and P1 trabecular bone and there was no difference in CatK staining intensity between the two bone types
There was a significant increase in the number of CatK-positive osteoclasts per bone surface in the P1 compared to the TC trabecular bone data (Figure 1B)
Summary
Cathepsin K (CatK) has become a major therapeutic target for the treatment of bone loss from osteoporosis[1], with potential for use in other diseases associated with bone resorption. Cathepsin K inhibition ameliorated the inflammatory response of equine bone marrow mononuclear cells stimulated by Toll like receptors (TLR) -4 and TLR-9 ligands in vitro along with evidence of suppressed bone resorption and increased bone formation in vivo due to repeated VEL-0230 administration in healthy exercising horses[9,10]. The precise role of CatK in the immune system is unclear and maybe attributed, in part, to the location and tight integration between the bone and bone marrow. The latter constitutes the body reserve for immune, stem and progenitor cells
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