Role of matrix metalloproteinase-10 in the BMP-2 inducing osteoblastic differentiation
Role of matrix metalloproteinase-10 in the BMP-2 inducing osteoblastic differentiation
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DOI：
10.1507/endocrj.ej13-0270
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发表时间：
2013-12-01
影响因子：
2
通讯作者：
Kaji, Hiroshi
中科院分区：
文献类型：
--
作者：
Mao, Li;Yano, Masato;Kaji, Hiroshi
进行性骨化性纤维发育不良（FOP）是一种骨骼肌进行性异位骨化的骨骼疾病。在大多数FOP患者中发现了导致骨形态发生蛋白（BMP）1型受体[ALK 2（R206 H）]组成性激活的突变。然而，FOP中肌肉异位骨化的细节和基质金属蛋白酶-10（MMP-10）在骨中的作用仍有待充分阐明。在本研究中，我们研究了MMP-10在小鼠成肌细胞C2 C12细胞向成骨细胞分化中的作用。MMP-10作为一种因子被提取，其表达通过ALK 2（R206 H）转染在C2 C12细胞中最广泛地增强。MMP-10可显著增加C2 C12细胞中Osterix、1型胶原、碱性磷酸酶（ALP）和骨钙素mRNA的水平，以及BMP-2所增强的ALP活性。此外，通过siRNA降低内源性MMP-10水平显著降低了这些细胞中由BMP-2增强的Runx 2、Osterix、1型胶原、ALP和骨钙素mRNA的水平。此外，MMP-10增加了Smad 1/5/8的磷酸化，并增强了BMP-2诱导的Smad 6和Smad 7 mRNA的水平。总之，本研究首次证明MMP-10通过与BMP信号通路相互作用促进成肌细胞向成骨细胞的分化。MMP-10可能在FOP的异位骨化中起重要作用。
Fibrodysplasia ossificans progressiva (FOP) is a skeletal disorder with progressive heterotopic ossification in skeletal muscle. A mutation causing constitutive activation in a bone morphogenetic protein (BMP) type 1 receptor [ALK2(R206H)] is found in most patients with FOP. However, the details in the heterotopic ossification of muscle in FOP and the role of matrix metalloproteinase-10 (MMP-10) in bone remain to be fully elucidated. In the present study, we investigated the role of MMP-10 in the differentiation of mouse myoblastic C2C12 cells into osteoblasts. MMP-10 was extracted as a factor, whose expression was most extensively enhanced by ALK2 (R206H) transfection in C2C12 cells. MMP-10 significantly augmented the levels of Osterix, type 1 collagen, alkaline phosphatase (ALP) and osteocalcin mRNA as well as ALP activity enhanced by BMP-2 in C2C12 cells. Moreover, a reduction in endogenous MMP-10 levels by siRNA significantly decreased the levels of Runx2, Osterix, type 1 collagen, ALP and osteocalcin mRNA enhanced by BMP-2 in these cells. In addition, MMP-10 increased the phosphorylation of Smad1/5/8 as well as enhanced the levels of Smad6 and Smad7 mRNA induced by BMP-2. In conclusion, the present study first demonstrated that MMP-10 promotes the differentiation of myoblasts into osteoblasts by interacting with the BMP signaling pathway. MMP-10 may play some important role in the heterotopic ossification of muscle in FOP.