Role of matrix metalloproteinase-10 in the BMP-2 inducing osteoblastic differentiation.
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.
Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, Osaka-Sayama 589-8511, Japan.
Li
L
Mao
Masato
M
Yano
Naoyuki
N
Kawao
Yukinori
Y
Tamura
Kiyotaka
K
Okada
Hiroshi
H
Kaji
D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism; D019943:Amino Acid Substitution; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation; D002460:Cell Line; D024042:Collagen Type I / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D053506:Matrix Metalloproteinase 10 / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D050505:Mutant Proteins / Q000819:agonists / Q000378:metabolism; D032446:Myoblasts / Q000166:cytology / Q000201:enzymology / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology* / Q000201:enzymology / Q000378:metabolism; D015675:Osteocalcin / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D015398:Signal Transduction; D051905:Smad6 Protein / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D051906:Smad7 Protein / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000819:agonists / Q000235:genetics / Q000378:metabolism
C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D024042:Collagen Type I; D050505:Mutant Proteins; D011994:Recombinant Proteins; D051905:Smad6 Protein; C497803:Smad6 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; D015675:Osteocalcin; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I; C498211:BMPR1A protein, human; D052005:Bone Morphogenetic Protein Receptors, Type I; C511770:MMP10 protein, human; D053506:Matrix Metalloproteinase 10