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 () and Sundeep Khosla ()
Additional contact information
Megan M. Weivoda: Mayo Clinic College of Medicine and Science
Chee Kian Chew: Mayo Clinic College of Medicine and Science
David G. Monroe: Mayo Clinic College of Medicine and Science
Joshua N. Farr: Mayo Clinic College of Medicine and Science
Elizabeth J. Atkinson: Mayo Clinic College of Medicine and Science
Jennifer R. Geske: Mayo Clinic College of Medicine and Science
Brittany Eckhardt: Mayo Clinic College of Medicine and Science
Brianne Thicke: Mayo Clinic College of Medicine and Science
Ming Ruan: Mayo Clinic College of Medicine and Science
Amanda J. Tweed: Mayo Clinic College of Medicine and Science
Louise K. McCready: Mayo Clinic College of Medicine and Science
Robert A. Rizza: Mayo Clinic College of Medicine and Science
Aleksey Matveyenko: Mayo Clinic College of Medicine and Science
Moustapha Kassem: University of Southern Denmark
Thomas Levin Andersen: University of Southern Denmark
Adrian Vella: Mayo Clinic College of Medicine and Science
Matthew T. Drake: Mayo Clinic College of Medicine and Science
Bart L. Clarke: Mayo Clinic College of Medicine and Science
Merry Jo Oursler: Mayo Clinic College of Medicine and Science
Sundeep Khosla: Mayo Clinic College of Medicine and Science

Nature Communications, 2020, vol. 11, issue 1, 1-13

Abstract: Abstract 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.

Date: 2020
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DOI: 10.1038/s41467-019-14003-6

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