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J Bone Miner Res. 2017 Feb;32(2):294-308. doi: 10.1002/jbmr.2973. Epub 2016 Dec 5.

Plasmin Prevents Dystrophic Calcification After Muscle Injury.

Author information

  • 1Department of Orthopaedics and Rehabilitation, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 2Department of Orthopaedics, Tokyo Medical Dental University, Tokyo, Japan.
  • 3School of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 4Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 5Ionis Pharmaceuticals, Carlsbad, CA, USA.
  • 6Department of Experimental Hematology, Cincinnati Children's Hospital, Cincinnati, OH, USA.
  • 7Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 8Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 9Vanderbilt Center for Bone Biology, Vanderbilt University Medical Center, Nashville, TN, USA.

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.

KEYWORDS:

DISORDERS OF CALCIUM/PHOSPHATE; INJURY/FRACTURE HEALING-ORTHOPEDICS; PRECLINICAL STUDIES; SKELETAL MUSCLE; THERAPEUTICS-OTHER

PMID:
27530373
DOI:
10.1002/jbmr.2973
[PubMed - in process]
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