Language
English
Publication Date
9-5-2024
Journal
Bone Research
DOI
10.1038/s41413-024-00352-6
PMID
39231935
PMCID
PMC11375055
PubMedCentral® Posted Date
9-5-2024
PubMedCentral® Full Text Version
Post-print
Abstract
Osteoporosis remains incurable. The most widely used antiresorptive agents, bisphosphonates (BPs), also inhibit bone formation, while the anabolic agent, teriparatide, does not inhibit bone resorption, and thus they have limited efficacy in preventing osteoporotic fractures and cause some side effects. Thus, there is an unmet need to develop dual antiresorptive and anabolic agents to prevent and treat osteoporosis. Hydroxychloroquine (HCQ), which is used to treat rheumatoid arthritis, prevents the lysosomal degradation of TNF receptor-associated factor 3 (TRAF3), an NF-κB adaptor protein that limits bone resorption and maintains bone formation. We attempted to covalently link HCQ to a hydroxyalklyl BP (HABP) with anticipated low antiresorptive activity, to target delivery of HCQ to bone to test if this targeting increases its efficacy to prevent TRAF3 degradation in the bone microenvironment and thus reduce bone resorption and increase bone formation, while reducing its systemic side effects. Unexpectedly, HABP-HCQ was found to exist as a salt in aqueous solution, composed of a protonated HCQ cation and a deprotonated HABP anion. Nevertheless, it inhibited osteoclastogenesis, stimulated osteoblast differentiation, and increased TRAF3 protein levels in vitro. HABP-HCQ significantly inhibited both osteoclast formation and bone marrow fibrosis in mice given multiple daily PTH injections. In contrast, HCQ inhibited marrow fibrosis, but not osteoclast formation, while the HABP alone inhibited osteoclast formation, but not fibrosis, in the mice. HABP-HCQ, but not HCQ, prevented trabecular bone loss following ovariectomy in mice and, importantly, increased bone volume in ovariectomized mice with established bone loss because HABP-HCQ increased bone formation and decreased bone resorption parameters simultaneously. In contrast, HCQ increased bone formation, but did not decrease bone resorption parameters, while HABP also restored the bone lost in ovariectomized mice, but it inhibited parameters of both bone resorption and formation. Our findings suggest that the combination of HABP and HCQ could have dual antiresorptive and anabolic effects to prevent and treat osteoporosis.
Keywords
Animals, Ovariectomy, Female, Mice, Hydroxychloroquine, Diphosphonates, Bone Resorption, Bone Density Conservation Agents, Mice, Inbred C57BL, Anabolic Agents, Osteogenesis, Osteoporosis, Osteoclasts, Osteoporosis, Bone
Published Open-Access
yes
Recommended Citation
Yao, Zhenqiang; Ayoub, Akram; Srinivasan, Venkatesan; et al., "Hydroxychloroquine and a Low Antiresorptive Activity Bisphosphonate Conjugate Prevent and Reverse Ovariectomy-Induced Bone Loss in Mice Through Dual Antiresorptive and Anabolic Effects" (2024). Faculty, Staff and Students Publications. 8608.
https://digitalcommons.library.tmc.edu/baylor_docs/8608