Bone Abstracts

Survival of chronic diseases in childhood is often achieved utilizing glucocorticoids. However, the survival comes at a cost to the growing skeleton, resulting in impairment in the acquisition of peak bone mass and is the major etiology of secondary osteoporosis in children. We recently found that preosteoclasts secrete platelet derived growth factor type BB (PDGF-BB) to promote angiogenesis and osteogenesis during both modeling and remodeling. As glucocorticoid therapy affects both osteoclast bone resorption and osteoblast bone formation, we explored if disruption of osteoclast bone resorption via genetic loss of cathepsin K (Ctsk), which increases secretion of preosteoclast PDGF-BB, could protect the skeleton of young mice exposed to prednisolone. We first characterized the temporal osteoclast and osteoblast progenitor populations in global cathepsin K knockout (Ctsk^−/−) relative to wild type mice in both the primary and secondary spongiosa. Loss of cathepsin K activity resulted in increased trap positive cells in both the primary and secondary spongiosa and correlated with the increased bone volume seen in the Ctsk^−/− mice relative to wild type littermates at 2, 4, and 8 weeks of age. Osteoprogenitors were similarly increased at all time points, with a more significant difference noted in the secondary spongiosa compared to primary spongiosa. We then established a glucocorticoid-induced mouse model in young Ctsk^−/− mice and wild type littermates with prednisolone at 10 mg/m² per day beginning at 2 weeks of life and continuing for 4 weeks. Overall, the osteoporotic phenotype as assessed by microcomputed tomography noted in wild type mice treated with prednisolone relative to vehicle treatment was prevented in Ctsk^−/− mice treated with prednisolone relative to vehicle. Trap staining and co-staining with PDGF-BB demonstrated that osteoclast numbers decreased in response to prednisolone, whereas loss of cathepsin K ameliorated this decrease largely by increasing Trap-positive mononuclear cells in the bone marrow. Serum concentrations of PDGF-BB showed a similar pattern. The decreased angiogenesis and osteogenesis, as assessed by H-type vessels and osteocalcin staining, observed in wild type mice treated with prednisolone were attenuated in Ctsk^−/− mice treated with prednisolone. These data suggest that inhibition of osteoclast resorption that preserves osteoclast coupling factors may be a potential preventive treatment strategy against glucocorticoid-induced osteoporosis in the growing skeleton.

Funding: Pediatric Endocrine Society Clinical Scholar Award and US National Institute of Health 1K08AR064833.

Disclosure: The authors declared no competing interests.