Hymenialdisine: A Marine Natural Product That Acts on Both Osteoblasts and Osteoclasts and Prevents Estrogen-Dependent Bone Loss in Mice
Hymenialdisine: A Marine Natural Product That Acts on Both Osteoblasts and Osteoclasts and Prevents Estrogen-Dependent Bone Loss in Mice
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Hymenialdisine：一种海洋天然产物，可作用于成骨细胞和破骨细胞，防止小鼠雌激素依赖性骨质流失
DOI：
10.1002/jbmr.4025
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发表时间：
2020-04-22
影响因子：
6.2
通讯作者：
Xu, Jiake
中科院分区：
文献类型：
--
作者：
Wang, Qingqing;Chen, Delong;Xu, Jiake
破骨细胞（OC）活性过高以及成骨细胞（OB）功能相对较弱与溶骨性疾病密切相关，包括骨质疏松症、肿瘤诱导的骨质溶解和炎性骨侵蚀。很少有天然产品或化合物被证明对OC和OB都具有治疗作用，这限制了天然化合物临床应用的潜在发展。Hymenialdisine（HMD）是一种天然的蛋白激酶抑制剂，具有抗骨关节炎和抗癌作用。然而，HMD在OC、OB和骨质疏松症中的作用尚未得到很好的确定。在这里，我们发现，HMD不仅抑制破骨细胞，但也促进OB分化。HMD对RANKL诱导的OC形成、骨吸收和OC特异性基因表达具有剂量依赖性抑制作用。这些强抑制作用是通过阻断NF-κ B和MAPK信号通路以及NFATc 1表达实现的。此外，HMD可能通过激活碱性磷酸酶（ALP）和增强OB基质矿化来刺激OB分化。我们发现，HMD可以激活糖原合成酶激酶3 β（GSK-3 β）/β-连环蛋白/T细胞因子（TCF）/淋巴增强因子（LEF）信号通路，以上调Runx-2的表达，Runx-2是该通路中的主要转录因子。Runx-2的表达增加也与OB特异性基因Col 1a 1和骨钙素（OCN）的表达相关。此外，我们还评估了HMD在卵巢切除术（OVX）诱导的系统性骨丢失的雌性C57 BL/6 j小鼠模型中的治疗潜力。HMD显示出显著的防止骨体积（BV/TV）和骨小梁厚度（Tb.Th）减少的能力。总之，HMD在抑制OC相关的骨溶解和促进OB诱导的骨化方面具有显著的作用，提示HMD在骨质疏松症治疗中具有潜在的应用前景。(c)2020年美国骨与矿物质研究学会。
Excessive osteoclast (OC) activity together with relatively weak osteoblast (OB) function are strongly connected to osteolytic diseases, including osteoporosis, tumor-induced osteolysis, and inflammatory bone erosion. Very few natural products or compounds have been shown to exert therapeutic effects on both OCs and OBs, limiting the potential development of natural compounds for clinical application. Hymenialdisine (HMD) is a marine sponge-derived natural inhibitor of protein kinases with previously reported anti-osteoarthritis and anti-cancer properties. However, the roles of HMD in OCs, OBs, and osteoporosis have not yet been well established. Here, we found that HMD not only suppressed osteoclastogenesis but also promoted OB differentiation. HMD exerted dose-dependent inhibitory effects on RANKL-induced OC formation, bone resorption, and OC-specific gene expression. These strong inhibitory effects were achieved by blocking the NF-kappa B and MAPK signaling pathways, and NFATc1 expression. In addition, HMD potentially stimulated OB differentiation by activating alkaline phosphatase (ALP) and enhancing OB matrix mineralization. We found that HMD can activate the glycogen synthase kinase 3 beta (GSK-3 beta)/beta-catenin/T-cell factor (TCF)/lymphoid enhancer factor (LEF) signaling pathway to upregulate Runx-2 expression, the main transcription factor in this pathway. Increased expression of Runx-2 was also correlated with expression of the OB-specific genes Col1a1 and osteocalcin (Ocn). Furthermore, we also evaluated the therapeutic potential of HMD in a female C57BL/6j mouse model of ovariectomy (OVX)-induced systematic bone loss. HMD showed a remarkable ability to prevent decreases in bone volume (BV/TV) and trabecular thickness (Tb.Th). In summary, HMD exerts notable effects in inhibiting OC-related osteolysis and enhancing OB-induced ossification, suggesting the potential application of HMD in osteoporosis treatment. (c) 2020 American Society for Bone and Mineral Research.