title: Characterization of dystrophic calcification induced in mice by cardiotoxin.
abstract: Dystrophic calcifications often occur after injury, infection, or onset of certain rheumatic diseases. Treatment has been limited to surgical removal following failure of medical therapy. In an attempt to establish a reproducible animal model for dystrophic calcification that permitted the screening of potential interventions, we evaluated cardiotoxin (injury)-induced calcifications in three murine strains at both the cellular and ultrastructural levels. All osteopontin null mice and tumor necrosis factor receptor null mice on a C57B6 background had calcifications at days 3 and 7 after injury compared to 75% of wild-type C57B6 mice. There was no difference in mineral content among calcifications from the three mouse strains. Osteogenesis was suggested by the expression of osteocalcin, osterix, and alkaline phosphatase in calcified murine muscle tissue. Osteoclast-like cells facilitated the removal of transient dystrophic deposits (<28 days) in all models. However, none of the models showed an association of mineral crystals with collagen, suggesting that the deposits were not bone-like. The dystrophic mechanism was validated as cell death, and mitochondrial calcifications occurred soon after skeletal muscle injury in the three murine strains.
authors.affiliation: Center of Excellence in Clinical Immunology, Children's Memorial Research Center, 2300 Children's Plaza, Box 212, Chicago, IL 60614, USA. yongdong.zhao@cchmc.org
authors.forename: Yongdong
authors.initials: Y
authors.lastname: Zhao
authors.forename: Annette L
authors.initials: AL
authors.lastname: Urganus
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Spevak
authors.forename: Sheela
authors.initials: S
authors.lastname: Shrestha
authors.forename: Stephen B
authors.initials: SB
authors.lastname: Doty
authors.forename: Adele L
authors.initials: AL
authors.lastname: Boskey
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Pachman
mesh_terms: D000469:Alkaline Phosphatase / Q000235:genetics; D000818:Animals; D001857:Bone Matrix / Q000378:metabolism / Q000473:pathology; D002114:Calcinosis / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004179:Cobra Cardiotoxin Proteins / Q000633:toxicity*; D003094:Collagen / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008928:Mitochondria / Q000187:drug effects / Q000473:pathology; D028361:Mitochondrial Diseases / Q000139:chemically induced / Q000473:pathology / Q000503:physiopathology; D018482:Muscle, Skeletal / Q000187:drug effects / Q000473:pathology* / Q000503:physiopathology; D009135:Muscular Diseases / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics; D053495:Osteopontin / Q000235:genetics; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000235:genetics
chemical_list: D004179:Cobra Cardiotoxin Proteins; D018124:Receptors, Tumor Necrosis Factor; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; C506896:Spp1 protein, mouse; D014157:Transcription Factors; D053495:Osteopontin; D003094:Collagen; D000469:Alkaline Phosphatase
references.citation: J Electron Microsc (Tokyo). 2003;52(6):527-33
references.pmid: 14756240
references.citation: Toxicon. 1991;29(1):31-41
references.pmid: 1827547
references.citation: J Biol Chem. 2006 Jan 6;281(1):429-38
references.pmid: 16267055
references.citation: ANZ J Surg. 2003 Jul;73(7):556-8
references.pmid: 12864841
references.citation: Toxicon. 1991;29(12):1489-500
references.pmid: 1666202
references.citation: Calcif Tissue Res. 1970;5(3):261-9
references.pmid: 5433628
references.citation: J Bone Miner Res. 2005 Dec;20(12):2169-77
references.pmid: 16294270
references.citation: Connect Tissue Res. 2004;45(4-5):248-56
references.pmid: 15763934
references.citation: Toxicon. 1993 Jun;31(6):697-709
references.pmid: 8342169
references.citation: Biochem Pharmacol. 2005 Jan 1;69(1):87-95
references.pmid: 15588717
references.citation: J Bone Miner Res. 2003 Jun;18(6):1005-11
references.pmid: 12817752
references.citation: Vib Spectrosc. 2005 Jul 29;38(1-2):107-114
references.pmid: 16691288
references.citation: Biochem Biophys Res Commun. 1998 Aug 19;249(2):522-5
references.pmid: 9712729
references.citation: Biochem J. 2004 Mar 15;378(Pt 3):1083-7
references.pmid: 14678013
references.citation: Biochem Int. 1983 May;6(5):581-91
references.pmid: 6148942
references.citation: J Cell Physiol. 2004 Jan;198(1):155-67
references.pmid: 14584055
references.citation: Arthritis Rheum. 2006 Oct;54(10):3345-50
references.pmid: 17009308
references.citation: Circ Res. 2005 Apr 15;96(7):717-22
references.pmid: 15831823
references.citation: Lab Anim Sci. 1997 Feb;47(1):11-8
references.pmid: 9051642
references.citation: Clin Immunol. 2007 Nov;125(2):165-72
references.pmid: 17704000
references.citation: Bone. 2008 Dec;43(6):983-90
references.pmid: 18789408
references.citation: Arthritis Rheum. 2009 Apr 15;61(4):501-8
references.pmid: 19333978
references.citation: Toxicon. 1987;25(9):1003-10
references.pmid: 3433297
references.citation: Proc Natl Acad Sci U S A. 2003 Sep 30;100(20):11201-6
references.pmid: 14500910
references.citation: J Bone Miner Res. 2005 Jul;20(7):1168-76
references.pmid: 15940369
references.citation: Calcif Tissue Res. 1978 Aug 18;25(3):217-22
references.pmid: 709402
references.citation: Am J Physiol Cell Physiol. 2005 Nov;289(5):C1179-87
references.pmid: 16079187
references.citation: Ann Plast Surg. 1995 Feb;34(2):138-47
references.pmid: 7741431