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Calcif Tissue Int. 2018 Dec 4. doi: 10.1007/s00223-018-0502-5. [Epub ahead of print]

Trauma-Induced Nanohydroxyapatite Deposition in Skeletal Muscle is Sufficient to Drive Heterotopic Ossification.

Author information

1
Department of Orthopaedics and Rehabilitation, Vanderbilt University Medical Center, 1215 21st Ave. South, Suite 4200 MCE, South Tower, Nashville, TN, 37232, USA.
2
Department of Pharmacology, Vanderbilt University, 2200 Pierce Ave, Robinson Research Building, Nashville, TN, 37232, USA.
3
Department of Dermatology and Cutaneous Biology, Sidney Kimmel Medical College, Thomas Jefferson University, 233 South Tenth Street, Bluemle Life Sciences Building, Room 450, Philadelphia, PA, 19107, USA.
4
College of Arts and Science, Vanderbilt University, 301 Kirkland Hall, Nashville, TN, 37240, USA.
5
Department of Pediatrics, Vanderbilt University Medical Center, 4202 Doctor's Office Tower, 2200 Children's Way, Nashville, TN, 37232, USA.
6
Department of Pathology Microbiology and Immunology, Vanderbilt University Medical Center, 1161 21st Ave. South, Nashville, TN, 37232, USA.
7
Division of Cardiovascular Medicine, Vanderbilt University Medical Center, 2220 Pierce Ave, Preston Research Building, Nashville, TN, 37232, USA.
8
University of Nebraska Medical Center, Omaha, NE, USA.
9
Department of Orthopaedics and Rehabilitation, Vanderbilt University Medical Center, 1215 21st Ave. South, Suite 4200 MCE, South Tower, Nashville, TN, 37232, USA. Jon.schoenecker@vanderbilt.edu.
10
Department of Pathology Microbiology and Immunology, Vanderbilt University Medical Center, 1161 21st Ave. South, Nashville, TN, 37232, USA. Jon.schoenecker@vanderbilt.edu.
11
Department of Pediatrics, Vanderbilt University Medical Center, 4202 Doctor's Office Tower, 2200 Children's Way, Nashville, TN, 37232, USA. Jon.schoenecker@vanderbilt.edu.
12
Department of Pharmacology, Vanderbilt University, 2200 Pierce Ave, Robinson Research Building, Nashville, TN, 37232, USA. Jon.schoenecker@vanderbilt.edu.
13
, 2200 Pierce Ave, Robinson Research Building, Rm 454, Nashville, TN, 37232, USA. Jon.schoenecker@vanderbilt.edu.

Abstract

Heterotopic ossification (HO), or the pathologic formation of bone within soft tissues, is a significant complication following severe injuries as it impairs joint motion and function leading to loss of the ability to perform activities of daily living and pain. While soft tissue injury is a prerequisite of developing HO, the exact molecular pathology leading to trauma-induced HO remains unknown. Through prior investigations aimed at identifying the causative factors of HO, it has been suggested that additional predisposing factors that favor ossification within the injured soft tissues environment are required. Considering that chondrocytes and osteoblasts initiate physiologic bone formation by depositing nanohydroxyapatite crystal into their extracellular environment, we investigated the hypothesis that deposition of nanohydroxyapatite within damaged skeletal muscle is likewise sufficient to predispose skeletal muscle to HO. Using a murine model genetically predisposed to nanohydroxyapatite deposition (ABCC6-deficient mice), we observed that following a focal muscle injury, nanohydroxyapatite was robustly deposited in a gene-dependent manner, yet resolved via macrophage-mediated regression over 28 days post injury. However, if macrophage-mediated regression was inhibited, we observed persistent nanohydroxyapatite that was sufficient to drive the formation of HO in 4/5 mice examined. Together, these results revealed a new paradigm by suggesting the persistent nanohydroxyapatite, referred to clinically as dystrophic calcification, and HO may be stages of a pathologic continuum, and not discrete events. As such, if confirmed clinically, these findings support the use of early therapeutic interventions aimed at preventing nanohydroxyapatite as a strategy to evade HO formation.

KEYWORDS:

Abcc6; Dystrophic calcification; Heterotopic ossification; Nanohydroxyapatite; Skeletal muscle injury

PMID:
30515544
DOI:
10.1007/s00223-018-0502-5

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