Int J Biol Sci 2022; 18(2):572-584. doi:10.7150/ijbs.63505 This issue

Research Paper

Myokine Irisin promotes osteogenesis by activating BMP/SMAD signaling via αV integrin and regulates bone mass in mice

Yuan Xue1,2#, Sihan Hu1,2#, Chichi Chen1, Jiachen He1, Jie Sun1, Yesheng Jin2, Yuanshu Zhang2, Guoqing Zhu3✉, Qin Shi1✉, Yongjun Rui2✉

1. Department of Orthopedics, the First Affiliated Hospital of Soochow University, Orthopedics Institute of Soochow University, Medical College of Soochow University, Suzhou, Jiangsu, 215006, P. R. China.
2. Department of Orthopedics, Wuxi Ninth People's Hospital affiliated to Soochow University, Wuxi, Jiangsu, 214026, P. R. China.
3. Department of Physiology, Nanjing Medical University, 101 Longmian Avenue, Nanjing, Jiangsu, 211166, P. R. China.
# These authors contributed equally to this work.

This is an open access article distributed under the terms of the Creative Commons Attribution License ( See for full terms and conditions.
Xue Y, Hu S, Chen C, He J, Sun J, Jin Y, Zhang Y, Zhu G, Shi Q, Rui Y. Myokine Irisin promotes osteogenesis by activating BMP/SMAD signaling via αV integrin and regulates bone mass in mice. Int J Biol Sci 2022; 18(2):572-584. doi:10.7150/ijbs.63505. Available from

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Graphic abstract

Irisin is well-known to contribute to bone homeostasis due to its bidirectional regulation on osteogenesis and osteoclastogenesis. However, the mechanisms of irisin involved in mesenchymal stem/stromal cells (MSCs)-derived osteogenesis are still under investigated. Fibronectin type III domain-containing protein 5 (FNDC5) is the precursor protein of irisin, compare with wild type (WT) littermates, FNDC5-/- mice lost bone mass significantly, collectively evidenced by the decrease of bone mineral density (BMD), impaired bone formation and reduced N-terminal propertied of type I procollagen (P1NP) in sera. Meanwhile, the bone resorbing of FNDC5-/- mice has enhanced accompanied by increased tartrate phosphatase (TRAP) staining cells morphologically and cross-Linked C-telopeptide of type 1 collagen (CTX) level in sera. In vitro study showed that lack of irisin impeded the MSC-derived osteogenesis of FNDC5-/- mice. The addition of irisin promote the osteogenesis of WT and irisin-deficient MSCs, by activating αV integrin-induced ERK/STAT pathway, subsequently enhancing bone morphogenetic protein 2 (BMP2) expression and BMP/SMAD signaling activation. Taken together, these findings further indicate that irisin regulates bone homeostasis. Moreover, irisin promotes MSC-derived osteogenesis by binding to αV integrin and activating BMP/SMAD signaling consequently. Thus, irisin may be a promising therapeutic target for osteoporosis and bone defects.

Keywords: Irisin, mesenchymal stem/stromal cell, Osteogenesis, BMP/SMAD signaling, αV integrin.