Cav1.2 regulates osteogenesis of bone marrow-derived mesenchymal stem cells via canonical Wnt pathway in age-related osteoporosis
Cav1.2 regulates osteogenesis of bone marrow-derived mesenchymal stem cells via canonical Wnt pathway in age-related osteoporosis
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DOI：
10.1111/acel.12967
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发表时间：
2019-08-01
期刊：
影响因子：
7.8
通讯作者：
Jin, Yan
中科院分区：
文献类型：
--
作者：
Fei, Dongdong;Zhang, Yang;Jin, Yan
目的骨质疏松相关的骨量丢失是困扰老年人群的最常见疾病之一。骨髓间充质干细胞（BMMSCs）成骨分化能力的下降被认为是其中一个重要的介导因素。电压门控性钙通道（VGCC）在多种细胞生物学功能的调节中起重要作用，VGCC的破坏与多种年龄相关的细胞特征和全身症状有关。然而，VGCCs是否以及如何导致BMMSCs成骨分化能力的降低尚未完全阐明。方法筛选电压门控性钙通道相关基因，并在多种衰老模型中确定候选基因。通过功能获得和功能丧失实验，研究确定通道在BMMSCs成骨分化中的功能作用。探讨其分子机制，并进行体内外干预实验。结果Zmpste 24-/- BMMSCs中Ca（v）1.2表达下调，与成骨能力降低有关。Ca（v）1.2通过经典的Wnt/beta-catenin通路调控BMMSCs的成骨。此外，上调Ca（v）1.2的活性减轻Zmpste 24-/-小鼠的骨质疏松症症状。结论Zmpste 24-/- BMMSCs成骨分化障碍可能与Ca（v）1. 2表达降低，导致经典Wnt通路受到抑制有关。Bay K8644治疗通过靶向Ca（v）1.2通道改善受损的成骨分化能力，可能是治疗年龄相关性骨丢失的适用方法。
Aims Age-related bone mass loss is one of the most prevalent diseases that afflict the elderly population. The decline in the osteogenic differentiation capacity of bone marrow-derived mesenchymal stem cells (BMMSCs) is regarded as one of the central mediators. Voltage-gated Ca2+ channels (VGCCs) play an important role in the regulation of various cell biological functions, and disruption of VGCCs is associated with several age-related cellular characteristics and systemic symptoms. However, whether and how VGCCs cause the decreased osteogenic differentiation abilities of BMMSCs have not been fully elucidated. Methods Voltage-gated Ca2+ channels related genes were screened, and the candidate gene was determined in several aging models. Functional role of determined channel on osteogenic differentiation of BMMSCs was investigated through gain and loss of function experiments. Molecular mechanism was explored, and intervention experiments in vivo and in vitro were performed. Results We found that Ca(v)1.2 was downregulated in these aging models, and downregulation of Ca(v)1.2 in Zmpste24-/- BMMSCs contributed to compromised osteogenic capacity. Mechanistically, Ca(v)1.2 regulated the osteogenesis of BMMSCs through canonical Wnt/beta-catenin pathway. Moreover, upregulating the activity of Ca(v)1.2 mitigated osteoporosis symptom in Zmpste24-/- mice. Conclusion Impaired osteogenic differentiation of Zmpste24-/- BMMSCs can be partly attributed to the decreased Ca(v)1.2 expression, which leads to the inhibition of canonical Wnt pathway. Bay K8644 treatment could be an applicable approach for treating age-related bone loss by ameliorating compromised osteogenic differentiation capacity through targeting Ca(v)1.2 channel.