Exploration of the miR‐187‐3p/CNR2 pathway in modulating osteoblast differentiation and treating postmenopausal osteoporosis through mechanical stress

• Published in: The FASEB journal 2024-07, Vol.38 (13), p.e23776-n/a
• Main Authors: Zhang, Lei, Zeng, Canjun, Huang, Juanyu, Yan, Haohang, Jiang, Yutao, Li, Runguang
• Format: Article
• Language: English
• Subjects: Animals; Cell Differentiation; Cells, Cultured; CNR2; Female; Humans; mechanical stress; Mice; Mice, Inbred C57BL; MicroRNAs - genetics; MicroRNAs - metabolism; miR‐187‐3p; Osteoblasts - metabolism; Osteogenesis; osteogenic differentiation; osteoporosis; Osteoporosis, Postmenopausal - genetics; Osteoporosis, Postmenopausal - metabolism; Osteoporosis, Postmenopausal - pathology; Osteoporosis, Postmenopausal - therapy; Signal Transduction; Stress, Mechanical
• ISSN: 0892-6638; 1530-6860; 1530-6860
• DOI: 10.1096/fj.202400113RR

This study aimed to explore how mechanical stress affects osteogenic differentiation via the miR‐187‐3p/CNR2 pathway. To conduct this study, 24 female C57BL/6 mice, aged 8 weeks, were used and divided into four groups. The Sham and OVX groups did not undergo treadmill exercise, while the Sham + EX and OVX + EX groups received a 8‐week treadmill exercise. Post‐training, bone marrow and fresh femur samples were collected for further analysis. Molecular biology analysis, histomorphology analysis, and micro‐CT analysis were conducted on these samples. Moreover, primary osteoblasts were cultured under osteogenic conditions and divided into GM group and CTS group. The cells in the CTS group underwent a sinusoidal stretching regimen for either 3 or 7 days. The expression of early osteoblast markers (Runx2, OPN, and ALP) was measured to assess differentiation. The study findings revealed that mechanical stress has a regulatory impact on osteoblast differentiation. The expression of miR‐187‐3p was observed to decrease, facilitating osteogenic differentiation, while the expression of CNR2 increased significantly. These observations suggest that mechanical stress, miR‐187‐3p, and CNR2 play crucial roles in regulating osteogenic differentiation. Both in vivo and in vitro experiments have confirmed that mechanical stress downregulates miR‐187‐3p and upregulates CNR2, which leads to the restoration of distal femoral bone mass and enhancement of osteoblast differentiation. Therefore, mechanical stress promotes osteoblasts, resulting in improved osteoporosis through the miR‐187‐3p/CNR2 signaling pathway. These findings have broad prospect and provide molecular biology guidance for the basic research and clinical application of exercise in the prevention and treatment of PMOP. The proposed mechanisms are summarized. The pathway by which miR‐187‐3p/CNR2 regulates osteoblast osteogenic differentiation for the prevention and treatment of osteoporosis is outlined. Mechanical stress, through downregulation of miR‐187‐3p, could enhance the expression of CNR2, leading to increased expression of early osteoblast markers and prevented the bone loss, which may be an alternative option to serve as a promising candidate for the prevention and treatment of PMOP in the future.