Bone Abstracts (2015) 4 OP3 | DOI: 10.1530/boneabs.4.OP3

Increase of preosteoclasts and secretion of PDGF-BB by inhibition of cathepsin K activity increases mouse bone mass during development

Janet Crane1, Zixing Ye2, Hui Xie1,3, Zhuying Xia1,3 & Xu Cao1

1Johns Hopkins University School of Medicine, Baltimore, MD, USA; 2Peking Union Medical College, Beijing, China; 3Second Xiangya Hospital, Central South University, Changsha, China.

Objective: Accretion of bone mass in childhood is dependent on both bone modeling and remodeling. We recently found that preosteoclasts secrete platelet derived growth factor type BB (PDGF-BB) to promote angiogenesis coupling with osteogenesis during both modeling and remodeling. As secretion of PDGF-BB by preosteoclasts can be enhanced through inhibition of cathepsin K activity to increase bone mass in adults, we explored if increase of secretion of PDGF-BB by preosteoclasts could have similar effects on bone mass in young mice.

Methods: Bone parameters of global cathepsin K knockout (Ctsk-/-) mice aged 2, 4 and 8 weeks vs wild type littermates were assessed. Additionally, wild type mice were administered either the selective cathepsin k inhibitor, L-235, or vehicle intraperitoneally 5 days per week from age 2 to 6 weeks. Microcomputed tomography and histological analysis with tartrate resistance acid phosphatase staining and immunostaining for osterix and osteocalcin were analyzed.

Results: Ctsk−/− mice were found to have a statistically significant increase in bone trabecular volume and osteoclast and osteoblast numbers at 2, 4, and 8 weeks of age compared to their aged-matched wild type littermates. Wild type mice treated with L-235 from 2–6 weeks of age showed a statistically significantly higher bone volume per tissue volume and trabecular number with decreased trabecular spacing compared to vehicle-treated wild type littermates. No difference was noted in cortical bone parameters. Histologic studies confirmed similar findings as those to ovariectomized-mouse models with an increase in preosteoclast numbers as well as osteoprogenitors and mature osteoblasts compared to vehicle-treated wild type littermates.

Conclusion: These preliminary data suggest that cathepsin K inhibition can increase bone mass by increasing preosteoclasts and secretion of PDGF-BB in young mice. Future studies are underway to study the ability to enhance bone mass in young osteoporotic animal models.

Funding sources: NIH/NIAMS 1K08AR064833-01A1, Pediatric Endocrine Society Clinical Scholar Award.

Disclosure: The authors declared no competing interests.

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