2. Academic Validation
  3. HA15 alleviates bone loss in ovariectomy-induced osteoporosis by targeting HSPA5

HA15 alleviates bone loss in ovariectomy-induced osteoporosis by targeting HSPA5

  • Exp Cell Res. 2021 Sep 15;406(2):112781. doi: 10.1016/j.yexcr.2021.112781.
Chao Han 1,  Kegong Xie 1,  Chengliang Yang 1,  Fan Zhang 1,  Qingyang Liang 1,  Changgong Lan 1,  Jian Chen 1,  Ke Huang 1,  Jia Liu 2,  Kai Li 3,  Yujin Tang 4,  Liqiang Wang 5
Affiliations

Affiliations

  • 1 Department of Orthopaedics, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, PR China; Youjiang Medical University for Nationalities, Baise, Guangxi, PR China.
  • 2 Department of Orthopaedics, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, PR China; Youjiang Medical University for Nationalities, Baise, Guangxi, PR China. Electronic address: liujia@ymcn.edu.cn.
  • 3 The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong Provincial Key Laboratory of Bone and Joint Degeneration Diseases, Guangdong, PR China. Electronic address: lk516433415@smu.edu.cn.
  • 4 Department of Orthopaedics, Affiliated Hospital of Youjiang Medical University for Nationalities, Baise, Guangxi, PR China; Youjiang Medical University for Nationalities, Baise, Guangxi, PR China. Electronic address: tangyujin@ymcn.edu.cn.
  • 5 State Key Laboratory of Metal Matrix Composites, School of Material Science and Engineering, Shanghai Jiao Tong University, Shanghai, 200240, China.
PMID: 34400174 DOI: 10.1016/j.yexcr.2021.112781
Abstract

The imbalance between osteogenesis and adipogenesis in the bone marrow is the main characteristic of osteoporosis (OP). Thus, exploring regulation of the differentiation of bone marrow stromal cells (BMSCs) into osteoblasts and adipocytes is important to identify novel targets for the treatment of OP. In the present study, the master regulator of endoplasmic reticulum (ER) stress, heat shock protein family A (HSP70) member 5 (HSPA5) was shown to significantly accumulate in osteoblasts and adipocytes, but not in osteoclasts in bone sections from aged and postmenopausal OP mice. In vitro study revealed that HSPA5 negatively modulated osteogenic differentiation and positively promoted adipogenic differentiation, and that targeting HSPA5 with its inhibitor HA15 enhanced osteogenic differentiation and inhibited adipogenic differentiation. Also, HA15 treatment induces ER stress and Autophagy, and decreases Apoptosis in cells. We constructed a postmenopausal OP model in mice with ovariectomy surgery, and treated the mice with HA15. The results showed that HA15 treatment induced appropriate ER stress, activated Autophagy and decreased Apoptosis in osteoblasts, thereby alleviating bone loss in vivo. Our results indicated that HSPA5 participated in OP pathogenesis by regulating the differentiation of BMSCs. HSPA5 may serve as a new target for the treatment of OP, and targeting HSPA5 with HA15 prevents the progression of OP and provides a candidate therapeutic molecule for postmenopausal OP.

Keywords

Bone marrow stromal cells; ER stress; HA15; Heat shock protein family A (Hsp70) member 5; Osteoporosis.

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