期刊
JOURNAL OF BONE AND MINERAL RESEARCH
卷 32, 期 2, 页码 294-308出版社
WILEY
DOI: 10.1002/jbmr.2973
关键词
INJURY/FRACTURE HEALING-ORTHOPEDICS; SKELETAL MUSCLE; THERAPEUTICS-OTHER; DISORDERS OF CALCIUM/PHOSPHATE; PRECLINICAL STUDIES
资金
- Fighting Duchenne Foundation
- National Institutes of Health [5T32 HL007751, 5T32 GM007628, 1R03AR065762 - 01A1, S10RR027631, 3T32DK007061-41S1]
- Vanderbilt Institute for Clinical and Translational Grant [VR6261]
- Orthopaedic Trauma Association, Resident Grant
- Howard Hughes Medical Institute, Medical Fellowship
- Vanderbilt Orthopaedic Institute, Research Grant
- Caitlin Lovejoy Fund
- Grants-in-Aid for Scientific Research [16K10848] Funding Source: KAKEN
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 (alpha 2-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. (C) 2016 American Society for Bone and Mineral Research.
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