Erythropoietin-Induced Changes in Bone and Bone Marrow in Mouse Models of Diet-Induced Obesity

Int J Mol Sci. 2020 Feb 28;21(5):1657. doi: 10.3390/ijms21051657.

Abstract

Obesity remodels bone and increases bone marrow adipocytes (BMAT), which negatively regulate hematopoiesis and bone. Reduced BMAT could restore altered hematopoiesis and bone features. We analyzed the potential of erythropoietin (EPO), the cytokine required for erythropoiesis, to inhibit BMAT in C57BL6/J mice fed four weeks of a high-fat diet (HFD). Acute EPO administration markedly decreased BMAT in regular chow diet (RCD) and HFD-fed mice, without affecting whole body fat mass. Micro-CT analysis showed EPO reduced trabecular bone in RCD- and HFD-fed mice, but EPO-treated HFD-fed mice maintained cortical bone mineral density and cortical bone volume, which was reduced on RCD. Despite achieving similar increased hematocrits with BMAT loss in RCD- and HFD-fed mice treated with EPO, decreased bone marrow cellularity was only observed in RCD-fed mice concomitant with an increasing percentage of bone marrow erythroid cells. In contrast, in HFD-fed mice, EPO increased endothelial cells and stromal progenitors with a trend toward the normalization of marrow homeostasis. EPO administration increased c-terminal FGF23 and intact serum FGF23 only in HFD-fed mice. These data demonstrate the distinct EPO responses of bone and marrow in normal and obese states, accompanying EPO-induced loss of BMAT.

Keywords: FGF23; bone; bone marrow adipocyte; erythropoietin; obesity; osteoblast; osteoclast; osteocyte; stromal cells.

MeSH terms

  • Adipose Tissue / pathology
  • Animals
  • Bone Marrow / drug effects
  • Bone Marrow / pathology*
  • Bone and Bones / drug effects
  • Bone and Bones / pathology*
  • Cancellous Bone / drug effects
  • Cancellous Bone / pathology
  • Diet, High-Fat*
  • Disease Models, Animal
  • Erythropoietin / administration & dosage
  • Erythropoietin / pharmacology*
  • Female
  • Fibroblast Growth Factors / blood
  • Mice, Inbred C57BL
  • Obesity / blood
  • Obesity / pathology*
  • Osteoblasts / drug effects
  • Osteoblasts / metabolism
  • Osteoblasts / pathology
  • Osteoclasts / drug effects
  • Osteoclasts / metabolism
  • Osteoclasts / pathology
  • Osteocytes / drug effects
  • Osteocytes / pathology
  • Periosteum / pathology

Substances

  • Erythropoietin
  • Fibroblast Growth Factors
  • fibroblast growth factor 23