Higenamine Promotes Osteogenesis Via IQGAP1/SMAD4 Signaling Pathway and Prevents Age- and Estrogen-Dependent Bone Loss in Mice

IF 5.1 1区医学 Q1 ENDOCRINOLOGY & METABOLISM

Journal of Bone and Mineral Research Pub Date : 2023-03-12 DOI:10.1002/jbmr.4800

Hui Dong, Ronghan Liu, Ke Zou, Zhengxin Jin, Jianning Kang, Ying Zhang, Xiaodi Zhang, Zhengfang Sun, Guilian Yu, Nana Huang, Morgan Bretches, Shang-You Yang, Bin Ning

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Abstract

Osteoporosis is a common bone disease caused by an imbalance of bone resorption and formation that results in a loss of total bone density. SMAD2/3 signal transduction is known to play a crucial role in osteogenic differentiation through transforming growth factor-beta (TGF-β). By screening a library of small-molecule compounds, the current study identifies higenamine (HG) as an active osteogenic agent that could be a therapeutic candidate for osteoporosis. In vitro data demonstrated that HG effectively induced expressions of osteogenic markers in mouse bone marrow stromal cell (BMSCs) and preosteoblastic cell cultures. Further, HG treatment resulted in enhanced bone formation and prevented accelerated bone loss on two animal models that mimic spontaneous senile osteoporosis and postmenopausal osteoporosis. IQ motif-containing GTPase-activating protein 1 (IQGAP1) was confirmed as a novel target of HG, where HG appears to bind to the Glu-1019 site of IQGAP1 to exert its osteogenic effects. Data subsequently suggested that HG promoted phosphorylation of SMAD2/3 and regulated the SMAD2/3 pathway by inhibiting SMAD4 ubiquitination. Overall, the findings highlight HG as a new small-molecule drug to promote bone formation through SMAD2/3 pathway in osteoporosis. © 2023 American Society for Bone and Mineral Research (ASBMR).

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Higenamine通过IQGAP1/SMAD4信号通路促进骨生成，防止小鼠年龄和雌激素依赖性骨质流失

骨质疏松症是一种常见的骨骼疾病，由骨吸收和形成的不平衡引起，导致总骨密度的损失。已知SMAD2/3信号转导通过转化生长因子-β (TGF-β)在成骨分化中起关键作用。通过筛选小分子化合物文库，目前的研究确定高铁胺(HG)是一种活性成骨剂，可能是骨质疏松症的治疗候选药物。体外数据表明，HG可有效诱导小鼠骨髓基质细胞(BMSCs)和成骨前细胞培养物中成骨标志物的表达。此外，在模拟自发性老年性骨质疏松症和绝经后骨质疏松症的两种动物模型中，HG治疗可促进骨形成并防止加速骨质流失。含有IQ基序的gtpase -激活蛋白1 (IQGAP1)被证实是HG的新靶点，其中HG似乎与IQGAP1的Glu-1019位点结合以发挥其成骨作用。随后的数据表明，HG促进SMAD2/3的磷酸化，并通过抑制SMAD4泛素化调节SMAD2/3通路。总的来说，这些发现突出了HG作为一种新的小分子药物，通过SMAD2/3途径促进骨质疏松症的骨形成。©2023美国骨与矿物研究学会(ASBMR)。

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来源期刊

Journal of Bone and Mineral Research 医学-内分泌学与代谢

CiteScore

11.30

自引率

6.50%

发文量

257

审稿时长

2 months

期刊介绍： The Journal of Bone and Mineral Research (JBMR) publishes highly impactful original manuscripts, reviews, and special articles on basic, translational and clinical investigations relevant to the musculoskeletal system and mineral metabolism. Specifically, the journal is interested in original research on the biology and physiology of skeletal tissues, interdisciplinary research spanning the musculoskeletal and other systems, including but not limited to immunology, hematology, energy metabolism, cancer biology, and neurology, and systems biology topics using large scale “-omics” approaches. The journal welcomes clinical research on the pathophysiology, treatment and prevention of osteoporosis and fractures, as well as sarcopenia, disorders of bone and mineral metabolism, and rare or genetically determined bone diseases.