Osteoinductive activity of bisdemethoxycurcumin and its synergistic protective effect with human amniotic mesenchymal stem cells against ovariectomy-induced osteoporosis mouse model
Osteoinductive activity of bisdemethoxycurcumin and its synergistic protective effect with human amniotic mesenchymal stem cells against ovariectomy-induced osteoporosis mouse model
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DOI：
10.1016/j.biopha.2021.112605
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发表时间：
2022-01-03
影响因子：
7.5
通讯作者：
Xiao, Jian-Hui
中科院分区：
文献类型：
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作者：
Wei, Jin-Xing;Luo, Yi;Xiao, Jian-Hui
骨质疏松症是一种以骨骼脆弱和微结构退化为特征的常见疾病。然而，现有的常规药物表现出有限的疗效，并可能引起严重的不良反应;此外，新的基于干细胞的疗法还没有表现出足够的治疗效果。我们的假设是，适当的成骨诱导剂可能会提高其治疗效果。在这项研究中，我们发现bisdeme-thoxycurcurcumin（BDMC）刺激人羊膜间充质干细胞（hAMSCs）分化为成骨细胞，而不诱导细胞毒性。在此，BDMC增强了hAMSC中的钙沉积，同时促进成骨细胞分化的早期和晚期标志物的表达，包括ALP、runt相关转录因子2、osterix、COL 1-alpha 1、骨钙素和骨桥蛋白在转录和翻译水平上的表达。在机制上，发现BDMC激活JAK 2/STAT 3通路;而AG 490（JAK 2/STAT 3通路抑制剂）抑制BDMC功能。随后，我们发现BDMC和hAMSC的组合治疗对双侧卵巢切除诱导的骨质疏松小鼠模型具有积极的协同作用，包括抑制骨丢失和骨吸收，改善骨微结构。此外，BDMC抑制骨吸收标志物I型胶原C-末端肽和抗酒石酸酸性磷酸酶的产生，同时促进骨形成标志物OCN和I型前胶原N-末端前肽的血清水平。BDMC还能改善糖尿病小鼠的肝肾功能。总的来说，BDMC通过增强hAMSC成骨来改善骨质疏松症，并在骨质疏松症小鼠模型中表现出对肝脏和肾脏功能的保护作用。因此，BDMC可作为一种有效的辅助治疗，与hAMSC联合治疗是一种有前途的骨质疏松症治疗新方法。
Osteoporosis is a common disease characterized by skeletal fragility and microarchitectural deterioration. However, existing conventional drugs exhibit limited efficacy and can elicit severe adverse effects; moreover, and novel stem cell-based therapies have not exhibited sufficient therapeutic efficacy. Our hypothesis is that an appropriate osteogenic inducer may improve their therapeutic efficacy. In this study, we found that bisdeme-thoxycurcumin (BDMC) stimulates the differentiation of human amniotic mesenchymal stem cells (hAMSCs) into osteoblasts without inducing cytotoxicity. Here BDMC enhances calcium deposition in hAMSCs, while promoting the expression of early and late markers of osteoblast differentiation, including ALP, runt-related transcription factor 2, osterix, COL1-alpha 1, osteocalcin, and osteopontin at the transcriptional and translational levels. Mecha-nistically, BDMC was found to activate the JAK2/STAT3 pathway; whereas AG490 (JAK2/STAT3 pathway in-hibitor) inhibited BDMC functioning. Subsequently, we found that the combinatorial therapy of BDMC and hAMSC had a positive synergistic effect on osteoporotic mouse model induced by bilateral ovariectomy, including inhibiting bone loss and bone resorption and improving bone micro-architecture. Moreover, BDMC inhibited production of the bone resorption markers C-terminal telopeptide of type I collagen, and tartrate resistant acid phosphatase, while promoting serum levels of bone formation markers OCN, and procollagen I N-terminal propeptide. BDMC also improved liver and kidney function in osteoporotic mouse model. Collectively, BDMC improved osteoporosis by enhancing hAMSC osteogenesis and exhibited a protective effect on liver and kidney function in an osteoporotic mouse model. Hence, BDMC may serve as an effective adjuvant, and com-bined therapy with hAMSCs is a promising new approach toward osteoporosis treatment.