Journal
STEM CELLS TRANSLATIONAL MEDICINE
Volume 6, Issue 3, Pages 799-806Publisher
WILEY
DOI: 10.5966/sctm.2015-0365
Keywords
Bone; Mesenchymal stem cell; Tissue regeneration; Chondrogenesis; Heterotopic ossification; Extremity trauma
Categories
Funding
- Coller Society Research Fellowship, National Institutes of Health (NIH) Loan Repayment Program [F32AR06649901A1]
- Plastic Surgery Foundation
- Howard Hughes Medical Institute Medical Fellows Program
- NIH/National Institute of General Medical Sciences [K08GM109105-0]
- American Association of Plastic Surgery Academic Scholarship
- Association for Academic Surgery Roslyn Award
- American Association for the Surgery of Trauma Research & Education Foundation Scholarship
- International FOP Association
- American Association of Plastic Surgeons/Plastic Surgery Foundation pilot award
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Trauma-induced heterotopic ossification (HO) occurs after severe musculoskeletal injuries and burns, and presents a significant barrier to patient rehabilitation. Interestingly, the incidence of HO significantly increases with repeated operations and after resection of previous HO. Treatment of established heterotopic ossification is challenging because surgical excision is often incomplete, with evidence of persistent heterotopic bone. As a result, patients may continue to report the signs or symptoms of HO, including chronic pain, nonhealing wounds, and joint restriction. In this study, we designed a model of recurrent HO that occurs after surgical excision of mature HO in a mouse model of hind-limb Achilles' tendon transection with dorsal burn injury. We first demonstrated that key signaling mediators of HO, including bone morphogenetic protein signaling, are diminished in mature bone. However, upon surgical excision, we have noted upregulation of downstream mediators of osteogenic differentiation, including pSMAD 1/5. Additionally, surgical excision resulted in re-emergence of a mesenchymal cell population marked by expression of platelet-derived growth factor receptor-alpha (PDGFR alpha) and present in the initial developing HO lesion but absent in mature HO. In the recurrent lesion, these PDGFR alpha+ mesenchymal cells are also highly proliferative, similar to the initial developing HO lesion. These findings indicate that surgical excision of HO results in recurrence through similar mesenchymal cell populations and signaling mechanisms that are present in the initial developing HO lesion. These results are consistent with findings in patients that new foci of ectopic bone can develop in excision sites and are likely related to de novo formation rather than extension of unresected bone. (C) STEM CELLS TRANSLATIONAL MEDICINE
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