title: Plasmin Prevents Dystrophic Calcification After Muscle Injury.
abstract: Extensive or persistent calcium phosphate deposition within soft tissues after severe traumatic injury or major orthopedic surgery can result in pain and loss of joint function. The pathophysiology of soft tissue calcification, including dystrophic calcification and heterotopic ossification (HO), is poorly understood; consequently, current treatments are suboptimal. Here, we show that plasmin protease activity prevents dystrophic calcification within injured skeletal muscle independent of its canonical fibrinolytic function. After muscle injury, dystrophic calcifications either can be resorbed during the process of tissue healing, persist, or become organized into mature bone (HO). Without sufficient plasmin activity, dystrophic calcifications persist after muscle injury and are sufficient to induce HO. Downregulating the primary inhibitor of plasmin (α2-antiplasmin) or treating with pyrophosphate analogues prevents dystrophic calcification and subsequent HO in vivo. Because plasmin also supports bone homeostasis and fracture repair, increasing plasmin activity represents the first pharmacologic strategy to prevent soft tissue calcification without adversely affecting systemic bone physiology or concurrent muscle and bone regeneration. © 2016 American Society for Bone and Mineral Research.
authors.affiliation: Department of Orthopaedics and Rehabilitation, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Nicholas A
authors.initials: NA
authors.lastname: Mignemi
authors.affiliation: Department of Orthopaedics and Rehabilitation, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Orthopaedics, Tokyo Medical Dental University, Tokyo, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Yuasa
authors.affiliation: School of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Courtney E
authors.initials: CE
authors.lastname: Baker
authors.affiliation: Department of Orthopaedics and Rehabilitation, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Stephanie N
authors.initials: SN
authors.lastname: Moore
authors.affiliation: School of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Rivka C
authors.initials: RC
authors.lastname: Ihejirika
authors.affiliation: Department of Orthopaedics and Rehabilitation, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: William K
authors.initials: WK
authors.lastname: Oelsner
authors.affiliation: School of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Christopher S
authors.initials: CS
authors.lastname: Wallace
authors.affiliation: Department of Orthopaedics, Tokyo Medical Dental University, Tokyo, Japan.
authors.forename: Toshitaka
authors.initials: T
authors.lastname: Yoshii
authors.affiliation: Department of Orthopaedics, Tokyo Medical Dental University, Tokyo, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Okawa
authors.affiliation: Ionis Pharmaceuticals, Carlsbad, CA, USA.
authors.forename: Alexey S
authors.initials: AS
authors.lastname: Revenko
authors.affiliation: Ionis Pharmaceuticals, Carlsbad, CA, USA.
authors.forename: A Robert
authors.initials: AR
authors.lastname: MacLeod
authors.affiliation: Ionis Pharmaceuticals, Carlsbad, CA, USA.
authors.forename: Gourab
authors.initials: G
authors.lastname: Bhattacharjee
authors.affiliation: School of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Joey V
authors.initials: JV
authors.lastname: Barnett
authors.affiliation: Department of Orthopaedics and Rehabilitation, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Herbert S
authors.initials: HS
authors.lastname: Schwartz
authors.affiliation: Department of Experimental Hematology, Cincinnati Children's Hospital, Cincinnati, OH, USA.
authors.forename: Jay L
authors.initials: JL
authors.lastname: Degen
authors.affiliation: Department of Experimental Hematology, Cincinnati Children's Hospital, Cincinnati, OH, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Flick
authors.affiliation: Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Cates
authors.affiliation: Department of Orthopaedics and Rehabilitation, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.|Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.|Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, USA.
authors.forename: Jonathan G
authors.initials: JG
authors.lastname: Schoenecker
mesh_terms: D000818:Animals; D002114:Calcinosis / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism*; D054715:Cardiotoxins; D011756:Diphosphates / Q000494:pharmacology / Q000627:therapeutic use; D005341:Fibrinolysin / Q000172:deficiency / Q000378:metabolism*; D005342:Fibrinolysis / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects / Q000293:injuries* / Q000473:pathology / Q000503:physiopathology; D009999:Ossification, Heterotopic / Q000188:drug therapy / Q000473:pathology; D012038:Regeneration / Q000187:drug effects
chemical_list: D054715:Cardiotoxins; D011756:Diphosphates; D005341:Fibrinolysin
keywords: DISORDERS OF CALCIUM/PHOSPHATE; INJURY/FRACTURE HEALING-ORTHOPEDICS; PRECLINICAL STUDIES; SKELETAL MUSCLE; THERAPEUTICS-OTHER