Identification of osteoclast-osteoblast coupling factors in humans reveals links between bone and energy metabolism

Megan M. Weivoda, Chee Kian Chew, David G. Monroe, Joshua N. Farr, Elizabeth J. Atkinson, Jennifer R. Geske, Brittany Eckhardt, Brianne Thicke, Ming Ruan, Amanda J. Tweed, Louise K. McCready, Robert A. Rizza, Aleksey Matveyenko, Moustapha Kassem, Thomas Levin Andersen, Adrian Vella, Matthew T. Drake, Bart L. Clarke, Merry Jo Oursler*, Sundeep Khosla

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Bone remodeling consists of resorption by osteoclasts followed by formation by osteoblasts, and osteoclasts are a source of bone formation-stimulating factors. Here we utilize osteoclast ablation by denosumab (DMAb) and RNA-sequencing of bone biopsies from postmenopausal women to identify osteoclast-secreted factors suppressed by DMAb. Based on these analyses, LIF, CREG2, CST3, CCBE1, and DPP4 are likely osteoclast-derived coupling factors in humans. Given the role of Dipeptidyl Peptidase-4 (DPP4) in glucose homeostasis, we further demonstrate that DMAb-treated participants have a significant reduction in circulating DPP4 and increase in Glucagon-like peptide (GLP)-1 levels as compared to the placebo-treated group, and also that type 2 diabetic patients treated with DMAb show significant reductions in HbA1c as compared to patients treated either with bisphosphonates or calcium and vitamin D. Thus, our results identify several coupling factors in humans and uncover osteoclast-derived DPP4 as a potential link between bone remodeling and energy metabolism.

TidsskriftNature Communications
Antal sider13
StatusUdgivet - 7. jan. 2020


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