Department of Orthopedic Surgery, the First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
Department of Orthopedic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China.
FASEB J. 2023 Sep;37(9):e22987. doi: 10.1096/fj.202300488R.
Postmenopausal osteoporosis is associated with bone formation inhibition mediated by the impaired osteogenic differentiation potential of bone marrow mesenchymal stem cells (BMSCs). However, identifying and confirming the essential genes in the osteogenic differentiation of BMSCs and osteoporosis remain challenging. The study aimed at revealing the key gene that regulated osteogenic differentiation of BMSCs and led to osteoporosis, thus exploring its therapeutic effect in osteoporosis. In the present study, six essential genes related to the osteogenic differentiation of BMSCs and osteoporosis were identified, namely, fibrillin 2 (Fbn2), leucine-rich repeat-containing 17 (Lrrc17), heat shock protein b7 (Hspb7), high mobility group AT-hook 1 (Hmga1), nexilin F-actin-binding protein (Nexn), and endothelial cell-specific molecule 1 (Esm1). Furthermore, the in vivo and in vitro experiments showed that Hmga1 expression was increased during the osteogenic differentiation of rat BMSCs, while Hmga1 expression was decreased in the bone tissue of ovariectomized (OVX) rats. Moreover, the expression of osteogenic differentiation-related genes, the activity of alkaline phosphatase (ALP), and the number of mineralized nodules were increased after Hmga1 overexpression, which was partially reversed by a Wnt signaling inhibitor (DKK1). In addition, after injecting Hmga1-overexpressing lentivirus into the bone marrow cavity of OVX rats, the bone loss, and osteogenic differentiation inhibition of BMSCs in OVX rats were partially reversed, while osteoclast differentiation promotion of BMSCs in OVX rats was unaffected. Taken together, the present study confirms that Hmga1 prevents OVX-induced bone loss by the Wnt signaling pathway and reveals that Hmga1 is a potential gene therapeutic target for postmenopausal osteoporosis.
绝经后骨质疏松症与骨髓间充质干细胞（BMSCs）成骨分化潜能受损介导的骨形成抑制有关。然而，确定和确认 BMSCs 成骨分化中的关键基因和骨质疏松症仍然具有挑战性。本研究旨在揭示调控 BMSCs 成骨分化并导致骨质疏松症的关键基因，从而探索其在骨质疏松症中的治疗作用。在本研究中，鉴定出了与 BMSCs 成骨分化和骨质疏松症相关的六个关键基因，即原纤维蛋白 2（Fbn2）、富含亮氨酸重复序列 17（Lrrc17）、热休克蛋白 b7（Hspb7）、高迁移率族 AT 钩蛋白 1（Hmga1）、连接蛋白 F-肌动蛋白结合蛋白（Nexn）和内皮细胞特异性分子 1（Esm1）。此外，体内和体外实验表明，Hmga1 在大鼠 BMSCs 成骨分化过程中表达增加，而在去卵巢（OVX）大鼠的骨组织中表达减少。此外，过表达 Hmga1 后，成骨分化相关基因的表达、碱性磷酸酶（ALP）的活性和矿化结节的数量增加，而 Wnt 信号抑制剂（DKK1）部分逆转了这一现象。此外，在 OVX 大鼠骨髓腔内注射 Hmga1 过表达慢病毒后，部分逆转了 OVX 大鼠 BMSCs 的骨丢失和成骨分化抑制，但对 OVX 大鼠 BMSCs 的破骨细胞分化促进无影响。综上所述，本研究证实 Hmga1 通过 Wnt 信号通路防止 OVX 引起的骨丢失，并表明 Hmga1 是绝经后骨质疏松症的潜在基因治疗靶点。
