Bushenhuoxue formula promotes osteogenic differentiation of growth plate chondrocytes through β-catenin-dependent manner during osteoporosis
Bushenhuoxue formula promotes osteogenic differentiation of growth plate chondrocytes through β-catenin-dependent manner during osteoporosis
复制标题
补肾活血方通过β-catenin依赖性方式促进骨质疏松症生长板软骨细胞成骨分化
DOI：
10.1016/j.biopha.2020.110170
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发表时间：
2020-07-01
影响因子：
7.5
通讯作者：
Jin, Hongting
中科院分区：
文献类型：
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作者：
Xia, Chenjie;Zou, Zhen;Jin, Hongting
背景：补肾活血方在我国治疗骨质疏松症已有良好的临床疗效。本研究的目的是确定BSHXF对小鼠模型的抗骨质疏松作用和精确的分子机制。方法：10周龄雌性C57 BL/6 J小鼠进行卵巢切除术，并提供BSHXF的每日治疗。在手术后8周，收获股骨用于组织分析，包括μ CT、组织学、qRT-PCR和β-连环蛋白、ALP和FABP 4的免疫组织化学（IHC）染色。为了探讨β-连环蛋白在BSHXF抗骨质疏松作用中的作用，在β-连环蛋白条件性基因敲除小鼠中进行了上述相关实验。结果：卵巢切除（OVX）小鼠出现严重的骨质流失，生长板下软骨骨结合部脂肪过度堆积，ALP表达减少，FABP 4表达增加。BSHXF显著恢复了OVX诱导的生长板软骨细胞的异常成骨和脂肪生成，并激活了β-连环蛋白。此外，我们产生了生长板软骨细胞特异性β-连环蛋白敲除（β-连环蛋白（Gli 1 ER））小鼠，其在软骨-骨连接处表现出骨丢失和脂肪积累，与OVX小鼠相似。然而，BSHXF未能拯救β-catenin（Gli 1 ER）小鼠的骨质疏松样表型，表明BSHXF的抗骨质疏松作用主要通过β-catenin信号传导。BSHXF治疗后，β-catenin GluER小鼠ALP和FABP 4无明显恢复。结论：BSHXF主要通过β-catenin依赖性方式促进生长板软骨细胞的成骨分化来减轻骨质疏松。补肾活血方被认为是治疗骨质疏松症的新的候选药物。
Background: Bushenhuoxue formula (BSHXF) has shown excellent clinical effects on the treatment of osteoporosis in China. The aim of this study is to determine the anti-osteoporosis effects and precise molecular mechanisms of BSHXF on mouse models.Methods: Ten-week-old female C57BL/6 J mice were subjected to ovariectomy and provided a daily treatment of BSHXF. At 8 weeks post-surgery, the femurs were harvested for tissue analyses including mu CT, histology, qRT-PCR and immunohistochemical (IHC) staining of beta-catenin, ALP and FABP4. To investigate the role of beta-catenin in the anti-osteoporosis effects of BSHXF, relative experiments mentioned above were performed in beta-catenin conditional knockout mice.Results: Ovariectomized (OVX) mice presented severe bone loss and excessive fat accumulation in the chondroosseous junction underneath the growth plate, with decreased expression of ALP and increased expression of FABP4. BSHXF significantly recovered the OVX-induced abnormal osteogenesis and adipogenesis with the activation of beta-catenin in growth plate chondrocytes. Further, we generated growth plate chondrocyte-specific beta-catenin knockout (beta-catenin(Gli1ER)) mice that exhibited bone loss and fat accumulation in the chondro-osseous junction, similar to the OVX mice. However, BSHXF failed to rescue the osteoporosis-like phenotype in beta-catenin(Gli1ER) mice, indicating the anti-osteoporosis effects of BSHXF act mainly through beta-catenin signaling. No significant restoration of ALP and FABP4 was observed in beta-catenin GluER mice after the treatment of BSHXF.Conclusions: BSHXF attenuates osteoporosis by promoting osteogenic differentiation of growth plate chondrocytes mainly in beta-catenin-dependent manner. BSHXF is considered as a new candidate for the treatment of osteoporosis.