Nesfatin-1 Promotes the Osteogenic Differentiation of Tendon-Derived Stem Cells and the Pathogenesis of Heterotopic Ossification in Rat Tendons via the mTOR Pathway.

Kai Xu,Safwat Adel Abdo Moqbel,Lidong Wu,Chiyuan Ma,Yuzhe He,Zhanfeng Zhang,Lifeng Jiang,Yan Xiong,Mengyao Chen

doi:10.3389/fcell.2020.547342

Abstract

Heterotopic ossification (HO) is a pathological condition involved in tendinopathy. Adipokines are known to play a key role in HO of tendinopathy. Nesfatin-1, an 82-amino acid adipokine is closely reportedly associated with diabetes mellitus (DM), which, in turn, is closely related to tendinopathy. In the present study, we aimed to investigate the effects of nesfatin-1 on the osteogenic differentiation of tendon-derived stem cells (TDSCs) and the pathogenesis of tendinopathy in rats. In vitro, TDSCs were incubated in osteogenic induction medium for 14 days with different nesfatin-1 concentration. In vivo, Sprague Dawley rats underwent Achilles tenotomy to evaluate the effect of nesfatin-1 on tendinopathy. Our results showed that the expression of nesfatin-1 expression in tendinopathy patients was significantly higher than that in healthy subjects. Nesfatin-1 affected the cytoskeleton and reduced the migration ability of TDSCs in vitro. Furthermore, nesfatin-1 inhibited the expression of Scx, Mkx, and Tnmd and promoted the expression of osteogenic genes, such as COL1a1, ALP, and RUNX2; these results suggested that nesfatin-1 inhibits cell migration, adversely impacts tendon phenotype, promotes osteogenic differentiation of TDSCs and the pathogenesis of HO in rat tendons. Moreover, we observed that nesfatin-1 suppressed autophagy and activated the mammalian target of rapamycin (mTOR) pathway both in vitro and in vivo. The suppression of the mTOR pathway alleviated nesfatin-1-induced HO development in rat tendons. Thus, nesfatin-1 promotes the osteogenic differentiation of TDSC and the pathogenesis of HO in rat tendons via the mTOR pathway; these findings highlight a new potential therapeutic target for tendinopathy.

Highlights

Tendinopathy is a progressive disorder of the tendon, accounting for over 30% of all musculoskeletal consultations (AndarawisPuri et al, 2015)
We evaluated the expression of NUCB2 in human Tendon-derived stem cells (TDSCs) and investigated the effects of nesfatin-1 on osteogenic TDSCs differentiation and pathogenesis of Heterotopic ossification (HO) in rat tendons
The results showed that nesfatin-1 significantly inhibited the expression of SCX, mohawk homeobox (Mkx), and Tnmd (Figures 3A–C), which demonstrated that nesfatin-1 may affect TDSC phenotype maintenance

Summary

Introduction

Tendinopathy is a progressive disorder of the tendon, accounting for over 30% of all musculoskeletal consultations (AndarawisPuri et al, 2015). Tendinopathy is characterized by an increase in tendon thickness, stiffness, and tendon reinjury and a decrease in motor function (Burner et al, 2012; Rothan et al, 2013). Heterotopic ossification (HO) is a pathological condition that involves the formation of ectopic bone and often occurs during tendinopathy (Longo et al, 2018). Several risk factors are known to result in heterotopic tendon ossification, including obesity, age, sex, tendon vascularity, and gastrocnemius or soleus dysfunction (Longo et al, 2018). The osteogenic differentiation of TDSCs may account for tendon dysfunction and exacerbate the pathogenesis of tendinopathy

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