Leptin accelerates the pathogenesis of heterotopic ossification in rat tendon tissues via mTORC1 signaling.

Abstract

Leptin, an adipocyte-derived cytokine associated with bone metabolism, is believed to play a critical role in the pathogenesis of heterotopic ossification (HO). The effect and underlying action mechanism of leptin were investigated on osteogenic differentiation of tendon-derived stem cells (TDSCs) in vitro and the HO formation in rat tendons. Isolated rat TDSCs were treated with various concentrations of leptin in the presence or absence of mTORC1 signaling specific inhibitor rapamycin in vitro. A rat model with Achilles tenotomy was employed to evaluate the effect of leptin on HO formation together with or without rapamycin treatment. In vitro studies with TDSCs showed that leptin increased the expression of osteogenic biomarkers (alkaline phosphatase, runt-related transcription factor 2, osterix, osteocalcin) and enhanced mineralization of TDSCs via activating the mTORC1 signal pathway (as indicated by phosphorylation of p70 ribosomal S6 kinase 1 and p70 ribosomal S6). However, mTORC1 signaling blockade with rapamycin treatment suppressed leptin-induced osteogenic differentiation and mineralization. In vivo studies showed that leptin promoted HO formation in the Achilles tendon after tenotomy, and rapamycin treatment blocked leptin-induced HO formation. In conclusion, leptin can promote TDSC osteogenic differentiation and heterotopic bone formation via mTORC1 signaling in both vitro and vivo model, which provides a new potential therapeutic target for HO prevention.

• Authors: Huaji Jiang, Yuhui Chen, Guorong Chen, Xinggui Tian, Jiajun Tang, Lei Luo, Minjun Huang, Bin Yan, Xiang Ao, Wen Zhou, Liping Wang, Xiaochun Bai, Zhongmin Zhang, Liang Wang, Cory J Xian
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 233 Issue 2 Pg. 1017-1028 (Feb 2018) ISSN: 1097-4652 [Electronic] United States
• PMID: 28407241 (Publication Type: Journal Article)
• Copyright: © 2017 Wiley Periodicals, Inc.

Chemical References

• Core Binding Factor Alpha 1 Subunit
• Leptin
• Receptors, Leptin
• Runx2 protein, rat
• Sp7 protein, rat
• Transcription Factors
• Mechanistic Target of Rapamycin Complex 1

Topics

• Animals
• Cell Differentiation (drug effects)
• Cells, Cultured
• Core Binding Factor Alpha 1 Subunit (metabolism)
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Leptin (toxicity)
• Male
• Mechanistic Target of Rapamycin Complex 1 (metabolism)
• Ossification, Heterotopic (chemically induced, enzymology, pathology)
• Osteoblasts (drug effects, enzymology, pathology)
• Osteogenesis (drug effects)
• Phenotype
• Rats, Sprague-Dawley
• Receptors, Leptin (metabolism)
• Signal Transduction (drug effects)
• Stem Cells (drug effects, enzymology, pathology)
• Tendons (drug effects, enzymology, pathology)
• Transcription Factors (metabolism)