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

Sukanya Suresh,Soumyadeep Dey,Constance Tom Noguchi,Josue Caban Alvarez

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.

Highlights

In adults, bone marrow adipose tissue (BMAT) comprises 70% of bone marrow volume and accounts for 10% of total fat mass [1,2]
An increase in lean mass was observed in both phosphate-buffered saline (PBS) and EPO-administered high-fat diet (HFD)-fed mice compared to the regular chow diet (RCD)-fed mice, significance was achieved only in the comparisons between RCD–PBS and HFD–PBS (Figure 1C)
We evaluated the effects of EPO administration on BMAT, trabecular and cortical bone, as well as on the bone marrow cell population under HFD feeding conditions in female C5BL6/J mice

Summary

Introduction

Bone marrow adipose tissue (BMAT) comprises 70% of bone marrow volume and accounts for 10% of total fat mass [1,2]. BMAT originates from a subset of bone marrow stromal cells (BMSCs) called skeletal stem cells, which are the precursors of osteoblasts that form the mineralized bone matrix [4]. Conditions of excessive marrow adiposity, such as ageing [5], estrogen deficiency, osteoporosis [6], obesity [7], caloric restriction [8], radiation and chemotherapy [9] are associated with bone loss and skeletal fragility, suggesting an inverse relationship between BMAT and bone remodeling. Men with increased visceral fat and BMAT have reduced cortical bone parameters and lower bone mechanical strength [13]. In pathological conditions characterized by excessive fatty marrow, interventions that can reduce BMAT expansion could prevent the associated bone loss and promote hematopoiesis

Methods

Results

Conclusion