title: Fibrodysplasia ossificans progressiva-related activated activin-like kinase signaling enhances osteoclast formation during heterotopic ossification in muscle tissues.
abstract: Fibrodysplasia ossificans progressiva is characterized by extensive ossification within muscle tissues, and its molecular pathogenesis is responsible for the constitutively activating mutation (R206H) of the bone morphogenetic protein type 1 receptor, activin-like kinase 2 (ALK2). In this study, we investigated the effects of implanting ALK2 (R206H)-transfected myoblastic C2C12 cells into nude mice on osteoclast formation during heterotopic ossification in muscle and subcutaneous tissues. The implantation of ALK2 (R206H)-transfected C2C12 cells with BMP-2 in nude mice induced robust heterotopic ossification with an increase in the formation of osteoclasts in muscle tissues but not in subcutaneous tissues. The implantation of ALK2 (R206H)-transfected C2C12 cells in muscle induced heterotopic ossification more effectively than that of empty vector-transfected cells. A co-culture of ALK2 (R206H)-transfected C2C12 cells as well as the conditioned medium from ALK2 (R206H)-transfected C2C12 cells enhanced osteoclast formation in Raw264.7 cells more effectively than those with empty vector-transfected cells. The transfection of ALK2 (R206H) into C2C12 cells elevated the expression of transforming growth factor (TGF)-β, whereas the inhibition of TGF-β signaling suppressed the enhanced formation of osteoclasts in the co-culture with ALK2 (R206H)-transfected C2C12 cells and their conditioned medium. In conclusion, this study demonstrated that the causal mutation transfection of fibrodysplasia ossificans progressiva in myoblasts enhanced the formation of osteoclasts from its precursor through TGF-β in muscle tissues.
authors.affiliation: From the Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, 377-2, Ohnohigashi, Osakasayama 589-8511 and.
authors.forename: Masato
authors.initials: M
authors.lastname: Yano
authors.affiliation: From the Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, 377-2, Ohnohigashi, Osakasayama 589-8511 and.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kawao
authors.affiliation: the Life Science Research Institute, Kinki University, 377-2, Ohnohigashi, Osakasayama 589-8511, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Okumoto
authors.affiliation: From the Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, 377-2, Ohnohigashi, Osakasayama 589-8511 and.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Tamura
authors.affiliation: From the Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, 377-2, Ohnohigashi, Osakasayama 589-8511 and.
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Okada
authors.affiliation: From the Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, 377-2, Ohnohigashi, Osakasayama 589-8511 and hkaji@med.kindai.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kaji
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D020125:Mutation, Missense; D032446:Myoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation; D009221:Myositis Ossificans / Q000235:genetics*; D041681:NIH 3T3 Cells; D009999:Ossification, Heterotopic / Q000235:genetics / Q000378:metabolism*; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D010012:Osteogenesis; D051381:Rats; D015398:Signal Transduction; D040521:Subcutaneous Tissue / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D017077:Culture Media, Conditioned; D016212:Transforming Growth Factor beta; C425423:ACVR1 protein, human; D030201:Activin Receptors, Type I
keywords: Bone; Bone Morphogenetic Protein (BMP); Muscle; Osteoclast; Transforming Growth Factor β (TGF-β)