miR-196b-5p Regulates Osteoblast and Osteoclast Differentiation and Bone Homeostasis by Targeting SEMA3A
miR-196b-5p Regulates Osteoblast and Osteoclast Differentiation and Bone Homeostasis by Targeting SEMA3A
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DOI：
10.1002/jbmr.4834
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发表时间：
2023-06-08
影响因子：
6.2
通讯作者：
Wang，Baoli
中科院分区：
文献类型：
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作者：
Xie，Yan;Zhou，Jie;Wang，Baoli
miR-196 b-5 p在多种恶性肿瘤中发挥作用。我们最近报道了它在调节脂肪形成中的功能。然而，miR-196 b-5 p是否以及如何影响骨细胞和骨稳态仍有待澄清。在这项研究中，体外功能实验显示了miR-196 b-5 p对成骨细胞分化的抑制作用。机制探索显示，miR-196 b-5 p直接靶向semaphorin 3a（Sema 3a）并抑制Wnt/β-catenin信号传导。SEMA 3A减弱了由miR-196 b-5 p诱导的受损的骨生成。成骨细胞特异性miR-196 b转基因小鼠显示骨量显著减少。在转基因小鼠中，骨小梁成骨细胞减少，骨形成受到抑制，而破骨细胞、骨髓脂肪细胞和骨吸收标志物的血清水平增加。来自转基因小鼠的成骨祖细胞具有降低的SEMA 3A水平，并表现出延迟的成骨分化，而那些骨髓成骨祖细胞表现出增强的破骨细胞分化。miR-196 B-5 p和SEMA 3A相反地调节核因子-κB配体受体激活剂和骨保护素的表达。表达转基因的颅骨成骨细胞促进破骨细胞的生成，而过表达Sema 3a的成骨细胞抑制破骨细胞的生成。最后，体内骨髓转染miR-196 b-5 p抑制剂可减少卵巢切除术诱导的小鼠骨丢失。我们的研究已经确定miR-196 b-5 p在成骨细胞和破骨细胞分化中起关键作用，并调节骨稳态。抑制miR-196 b-5 p可能有利于改善骨质疏松症。© 2023 American Society for Bone and Mineral Research（ASBMR）. Abstract这项研究已经确定miR-196 b-5 p是成骨细胞和破骨细胞分化和骨稳态的关键调节因子。miR-196 b-5 p通过靶向SEMA 3A/β-catenin信号通路抑制成骨细胞分化。此外，它通过调节成骨细胞中SEMA 3A和RANKL/OPG的表达促进破骨细胞的形成。
miR‐196b‐5p plays a role in various malignancies. We have recently reported its function in regulating adipogenesis. However, it remains to be clarified whether and how miR‐196b‐5p affects bone cells and bone homeostasis. In this study, in vitro functional experiments showed an inhibitory effect of miR‐196b‐5p on osteoblast differentiation. Mechanistic explorations revealed that miR‐196b‐5p directly targeted semaphorin 3a (Sema3a) and inhibited Wnt/β‐catenin signaling. SEMA3A attenuated the impaired osteogenesis induced by miR‐196b‐5p. Osteoblast‐specific miR‐196b transgenic mice showed significant reduction of bone mass. Trabecular osteoblasts were reduced and bone formation was suppressed, whereas osteoclasts, marrow adipocytes, and serum levels of bone resorption markers were increased in the transgenic mice. The osteoblastic progenitor cells from the transgenic mice had decreased SEMA3A levels and exhibited retarded osteogenic differentiation, whereas those marrow osteoclastic progenitors exhibited enhanced osteoclastogenic differentiation. miR‐196b‐5p and SEMA3A oppositely regulated the expression of receptor activator of nuclear factor‐κB ligand and osteoprotegerin. The calvarial osteoblastic cells expressing the transgene promoted osteoclastogenesis, whereas the osteoblasts overexpressing Sema3a inhibited it. Finally, in vivo transfection of miR‐196b‐5p inhibitor to the marrow reduced ovariectomy‐induced bone loss in mice. Our study has identified that miR‐196b‐5p plays a key role in osteoblast and osteoclast differentiation and regulates bone homeostasis. Inhibition of miR‐196b‐5p may be beneficial for amelioration of osteoporosis. © 2023 American Society for Bone and Mineral Research (ASBMR).AbstractThis study has identified miR‐196b‐5p as a key modulator of osteoblast and osteoclast differentiation and bone homeostasis. miR‐196b‐5p suppresses the differentiation of osteoblasts through targeting SEMA3A/β‐catenin signaling. Additionally, it promotes osteoclast formation through modulating SEMA3A and RANKL/OPG expression in osteoblastic cells.