title: Role of osteoclasts in heterotopic ossification enhanced by fibrodysplasia ossificans progressiva-related activin-like kinase 2 mutation in mice.
abstract: Fibrodysplasia ossificans progressiva (FOP) is a disorder of skeletal malformations and progressive heterotopic ossification. The constitutively activating mutation (R206H) of the bone morphogenetic protein type 1 receptor, activin-like kinase 2 (ALK2), is responsible for the pathogenesis of FOP. Although transfection of the causal mutation of FOP into myoblasts enhances osteoclast formation by transforming growth factor-β (TGF-β), the role of osteoclasts in heterotopic ossification is unknown. We therefore examined the effects of alendronate, SB431542 and SB203580 on heterotopic ossification induced by the causal mutation of FOP. Total bone mineral content as well as numbers of tartrate-resistant acid phosphatase (TRAP)-positive multinucleated and alkaline phosphatase (ALP)-positive cells in heterotopic bone were significantly higher in muscle tissues implanted with ALK2 (R206H)-transfected mouse myoblastic C2C12 cells than in the tissues implanted with empty vector-transfected cells in nude mice. Alendronate, an aminobisphosphonate, did not affect total mineral content or numbers of TRAP-positive multinucleated and ALP-positive cells in heterotopic bone, which were enhanced by the implantation of ALK2 (R206H)-transfected C2C12 cells, although it significantly decreased serum levels of cross-linked C-telopeptide of type I collagen, a bone resorption index. Moreover, neither SB431542, an inhibitor of TGF-β receptor type I kinase, nor SB203580, an inhibitor of p38 mitogen-activated protein kinase, affected the increase in heterotopic ossification due to the implantation of ALK2 (R206H)-transfected C2C12 cells. In conclusion, the present study indicates that osteoclast inhibition does not affect heterotopic ossification enhanced by FOP-related mutation.
authors.affiliation: Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, 589-8511, Osaka, Japan.
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kawao
authors.affiliation: Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, 589-8511, Osaka, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Yano
authors.affiliation: Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, 589-8511, Osaka, Japan.
authors.forename: Yukinori
authors.initials: Y
authors.lastname: Tamura
authors.affiliation: Life Science Research Institute, Kinki University, Osaka, Japan.
authors.forename: Katsumi
authors.initials: K
authors.lastname: Okumoto
authors.affiliation: Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, 589-8511, Osaka, Japan.
authors.forename: Kiyotaka
authors.initials: K
authors.lastname: Okada
authors.affiliation: Department of Physiology and Regenerative Medicine, Kinki University Faculty of Medicine, 377-2 Ohnohigashi, Osakasayama, 589-8511, Osaka, Japan. hkaji@med.kindai.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kaji
mesh_terms: D030201:Activin Receptors, Type I / Q000235:genetics*; D019386:Alendronate / Q000494:pharmacology; D000469:Alkaline Phosphatase / Q000032:analysis / Q000097:blood; D000818:Animals; D001549:Benzamides / Q000494:pharmacology; D002118:Calcium / Q000097:blood; D002460:Cell Line; D024042:Collagen Type I / Q000097:blood; D004149:Dioxoles / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D032446:Myoblasts / Q000637:transplantation; D009221:Myositis Ossificans / Q000235:genetics*; D009999:Ossification, Heterotopic / Q000209:etiology*; D010010:Osteoclasts / Q000187:drug effects / Q000502:physiology*; D010455:Peptides / Q000097:blood; D010758:Phosphorus / Q000097:blood; D011725:Pyridines / Q000494:pharmacology
chemical_list: C459179:4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide; D001549:Benzamides; D024042:Collagen Type I; D004149:Dioxoles; D007093:Imidazoles; D010455:Peptides; D011725:Pyridines; C052929:collagen type I trimeric cross-linked peptide; D010758:Phosphorus; D030201:Activin Receptors, Type I; C498943:Acvr1 protein, mouse; D000469:Alkaline Phosphatase; C093642:SB 203580; D002118:Calcium; D019386:Alendronate
keywords: Fibrodysplasia ossificans progressiva; Heterotopic ossification; Muscle; Osteoclasts