Gain-of-function mutation in FGFR3 in mice leads to decreased bone mass by affecting both osteoblastogenesis and osteoclastogenesis
Gain-of-function mutation in FGFR3 in mice leads to decreased bone mass by affecting both osteoblastogenesis and osteoclastogenesis
复制标题
小鼠 FGFR3 功能获得性突变通过影响成骨细胞生成和破骨细胞生成导致骨量减少
DOI：
10.1093/hmg/ddp590
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发表时间：
2010-04-01
影响因子：
3.5
通讯作者：
Chen, Lin
中科院分区：
文献类型：
--
作者：
Su, Nan;Sun, Qidi;Chen, Lin
软骨发育不全（achdroplasia， ACH）是一种由成纤维细胞生长因子受体3 （FGFR3）功能获得性突变引起的短肢侏儒症。先前的研究表明，乙酰胆碱ACH患者的软骨形成受损，但FGFR3对成年期乙酰胆碱ACH患者骨形成和骨重塑的影响尚未得到充分研究。通过显微计算机断层扫描和组织形态学分析，我们发现2个月大的Fgfr3（G369C/+）小鼠（模拟人类乙酰胆碱ACH的小鼠模型）由于小梁骨体积和骨矿物质密度减少、骨矿化缺陷和破骨细胞数量和活性增加而导致骨量减少。与野生型小鼠骨髓基质细胞（BMSCs）原代培养物相比，Fgfr3（G369C/+）培养物的细胞增殖能力下降，成骨分化增强，包括碱性磷酸酶活性和成骨细胞标记基因表达上调，骨基质矿化程度降低。此外，我们的研究还表明，在Fgfr3（G369C/+）骨髓间充质干细胞中观察到的细胞增殖减少和成骨分化增强是由p38磷酸化上调引起的，Erk1/2活性增强是骨基质矿化受损的原因。此外，体外破骨细胞形成和骨吸收实验表明，Fgfr3（G369C/+）小鼠培养的骨髓细胞的破骨细胞数量和骨吸收面积增加。这些发现表明，FGFR3的功能获得突变通过调节成骨细胞和破骨细胞的活性导致骨量减少。我们的研究为乙酰胆碱形成的机制提供了新的见解。
Achondroplasia (ACH) is a short-limbed dwarfism resulting from gain-of-function mutations in fibroblast growth factor receptor 3 (FGFR3). Previous studies have shown that ACH patients have impaired chondrogenesis, but the effects of FGFR3 on bone formation and bone remodeling at adult stages of ACH have not been fully investigated. Using micro-computed tomography and histomorphometric analyses, we found that 2-month-old Fgfr3(G369C/+) mice (mouse model mimicking human ACH) showed decreased bone mass due to reduced trabecular bone volume and bone mineral density, defect in bone mineralization and increased osteoclast numbers and activity. Compared with primary cultures of bone marrow stromal cells (BMSCs) from wild-type mice, Fgfr3(G369C/+) cultures showed decreased cell proliferation, increased osteogenic differentiation including up-regulation of alkaline phosphatase activity and expressions of osteoblast marker genes, and reduced bone matrix mineralization. Furthermore, our studies also suggest that decreased cell proliferation and enhanced osteogenic differentiation observed in Fgfr3(G369C/+) BMSCs are caused by up-regulation of p38 phosphorylation and that enhanced Erk1/2 activity is responsible for the impaired bone matrix mineralization. In addition, in vitro osteoclast formation and bone resorption assays demonstrated that osteoclast numbers and bone resorption area were increased in cultured bone marrow cells derived from Fgfr3(G369C/+) mice. These findings demonstrate that gain-of-function mutation in FGFR3 leads to decreased bone mass by regulating both osteoblast and osteoclast activities. Our studies provide new insight into the mechanism underlying the development of ACH.