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

• Published in: Nature communications Vol. 11; no. 1; pp. 87 - 13
• Main Authors: Weivoda, Megan M., Chew, Chee Kian, Monroe, David G., Farr, Joshua N., Atkinson, Elizabeth J., Geske, Jennifer R., Eckhardt, Brittany, Thicke, Brianne, Ruan, Ming, Tweed, Amanda J., McCready, Louise K., Rizza, Robert A., Matveyenko, Aleksey, Kassem, Moustapha, Andersen, Thomas Levin, Vella, Adrian, Drake, Matthew T., Clarke, Bart L., Oursler, Merry Jo, Khosla, Sundeep
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07.01.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 38/91; 631/443/63; 692/163/2743/316/801; 82/79; Ablation; Aged; Aged, 80 and over; Animals; Biomedical materials; Bisphosphonates; Bone and Bones - metabolism; Bone growth; Bone Remodeling; Bone resorption; Calcium; Calcium-Binding Proteins - genetics; Calcium-Binding Proteins - metabolism; Coupling; Coupling factors; Denosumab - administration & dosage; Diabetes mellitus; Diabetes Mellitus, Type 2 - drug therapy; Diabetes Mellitus, Type 2 - genetics; Diabetes Mellitus, Type 2 - metabolism; Diabetes Mellitus, Type 2 - physiopathology; Dipeptidyl Peptidase 4 - genetics; Dipeptidyl Peptidase 4 - metabolism; Dipeptidyl-peptidase IV; Energy metabolism; Energy Metabolism - drug effects; Female; Gene sequencing; Glucagon; Homeostasis; Humanities and Social Sciences; Humans; Metabolism; Middle Aged; Monoclonal antibodies; multidisciplinary; Osteoblasts; Osteoblasts - drug effects; Osteoblasts - metabolism; Osteoclasts; Osteoclasts - drug effects; Osteoclasts - metabolism; Osteogenesis; Peptidase; Post-menopause; Prospective Studies; Repressor Proteins - genetics; Repressor Proteins - metabolism; Ribonucleic acid; RNA; Science; Science (multidisciplinary); Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Vitamin D
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-019-14003-6

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. Anti-resorptive bone therapies also inhibit bone formation, as osteoclasts secrete factors that stimulate bone formation by osteoblasts. Here, the authors identify osteoclast-secreted factors that couple bone resorption to bone formation in healthy subjects, and show that osteoclast-derived DPP4 may be a factor coupling bone resorption to energy metabolism.