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

Nat Commun. 2020 Jan 7;11(1):87. 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.

Publication types

  • Randomized Controlled Trial
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Aged, 80 and over
  • Animals
  • Bone Remodeling
  • Bone and Bones / metabolism*
  • Calcium-Binding Proteins / genetics
  • Calcium-Binding Proteins / metabolism
  • Denosumab / administration & dosage
  • 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
  • Energy Metabolism* / drug effects
  • Female
  • Humans
  • Middle Aged
  • Osteoblasts / drug effects
  • Osteoblasts / metabolism*
  • Osteoclasts / drug effects
  • Osteoclasts / metabolism*
  • Prospective Studies
  • Repressor Proteins / genetics
  • Repressor Proteins / metabolism
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism


  • CCBE1 protein, human
  • CREG2 protein, human
  • Calcium-Binding Proteins
  • Repressor Proteins
  • Tumor Suppressor Proteins
  • Denosumab
  • Dipeptidyl Peptidase 4