HMGB2 is a novel adipogenic factor that regulates ectopic fat infiltration in skeletal muscles

Deokcheol Lee,Yoshitaka Hishikawa,Narantsog Choijookhuu,Etsuo Chosa,Katsuaki Sato,Noboru Taniguchi,Hidetaka Morinaga,Martin Lotz,Hiroaki Kataoka

doi:10.1038/s41598-018-28023-7

Abstract

Although various surgical procedures have been developed for chronic rotator cuff tear repair, the re-tear rate remains high with severe fat infiltration. However, little is known about the molecular regulation of this process. Mesenchymal stem cells (MSCs) in the intra-muscular space are origin of ectopic fat cells in skeletal muscle. We have previously shown that high-mobility group box 2 (HMGB2), which is a nuclear protein commonly associated with mesenchymal differentiation, is involved in the early articular cartilage degeneration. In this study, we addressed the role of HMGB2 in adipogenesis of MSCs and fat infiltration into skeletal muscles. HMGB2 was highly expressed in undifferentiated MSCs and co-localized with platelet-derived growth factor receptor α (PDGFRA) known as an MSC-specific marker, while their expressions were decreased during adipocytic differentiation. Under the deficiency of HMGB2, the expressions of adipogenesis-related molecules were reduced, and adipogenic differentiation is substantially impaired in MSCs. Moreover, HMGB2+ cells were generated in the muscle belly of rat supraspinatus muscles after rotator cuff transection, and some of these cells expressed PDGFRA in intra-muscular spaces. Thus, our findings suggest that the enhance expression of HMGB2 induces the adipogenesis of MSCs and the fat infiltration into skeletal muscles through the cascade of HMGB2-PDGFRA.

Highlights

Various surgical procedures have been developed for chronic rotator cuff tear repair, the re-tear rate remains high with severe fat infiltration
The genes involved in the Wnt signaling pathway, which reportedly inhibits the adipogenesis of MSCs27, were significantly increased in Hmgb2−/− Mesenchymal stem cells (MSCs) (Table 2)
Microarray analysis of bone marrow-derived MSCs from WT and Hmgb2−/− mice prompted the idea that high-mobility group box 2 (HMGB2), which is highly expressed in MSCs16, may be important for regulating adipogenesis

Summary

Introduction

Various surgical procedures have been developed for chronic rotator cuff tear repair, the re-tear rate remains high with severe fat infiltration. Under the deficiency of HMGB2, the expressions of adipogenesis-related molecules were reduced, and adipogenic differentiation is substantially impaired in MSCs. HMGB2+ cells were generated in the muscle belly of rat supraspinatus muscles after rotator cuff transection, and some of these cells expressed PDGFRA in intra-muscular spaces. HMGB1 and HMGB2 regulate various cellular activities, including transcription, DNA replication, and repair[12]. They bind to transcription factors, such as steroid hormone receptors, p53, p73, LEF1, and Runx[213–16], www.nature.com/scientificreports/. The function of HMGB2 in adipogenesis has not yet been elucidated

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