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

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.

Analyses of key mRNAs and lncRNAs for different osteo‐differentiation potentials of periodontal ligament stem cell and gingival mesenchymal stem cell

“…In addition, these mRNAs were involved in 51 signalling pathways, such as PI3K‐Akt signalling pathway, metabolic pathways, glycolysis/gluconeogenesis pathways and mTOR signalling pathway (Table ). Among these pathways, PI3K‐Akt signalling pathway, mTOR signalling pathway and so on have been reported to be positive regulators of osteogenic differentiation in MSCs, 30,31 so we speculated that the stronger osteo‐differentiation ability of hPDLSCs could be regulated by these signalling pathways. The top 10 GO terms (BP, CC, MF) and pathway terms are shown in Figure 4B and Figure 4E according to enrichment score.…”

“…Pathway analyses showed that these mRNAs were significantly enriched in 57 signalling pathways including aminoacyl‐tRNA biosynthesis pathway, metabolic pathways, biosynthesis of amino acid pathway, MAPK signalling pathway and so on (Figure 4D, Table ). Notably, MAPK signalling pathway has been reported to be a classical pathway that regulates the osteogenic differentiation of MSCs, 30,31 so we speculated that this pathway could play important roles in hPDLSCs and hGMSCs during osteogenic differentiation. The top 10 pathways are shown in Figure 4D according to enrichment score.…”

Spironolactone Ameliorates Senescence and Calcification by Modulating Autophagy in Rat Tendon‐Derived Stem Cells via the NF‐κB/MAPK Pathway

“…To determine the protective role of SP in vivo, an Achilles tenotomy rat model was used to mimic the in vitro tendinopathy model [ 6 , 7 , 32 ]. The flowchart for the animal procedures is shown in Figure 7(a) .…”

“…Since aging is a potential detrimental factor for tendon homeostasis, the effect of senescence on tendinopathy in TDSCs was investigated [ 44 , 45 ]. Our previous study reported that senescence in TDSCs is a characteristic of HO and chronic inflammation [ 6 , 7 ]. Similar to previous studies, more senescent TDSCs were detected under tendinopathic conditions.…”

“…Hence, we hypothesized that modulation of inflammation might be a potential therapeutic target for tendinopathy. Heterotopic ossification (HO) is another hallmark of tendinopathy [ 6 , 7 ]. It has been proposed that HO plays a significant role in the pathological progression of tendinopathy [ 8 ].…”