Surgical Excision of Heterotopic Ossification Leads to Re-Emergence of Mesenchymal Stem Cell Populations Responsible for Recurrence

Abstract

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‐α (PDGFRα) and present in the initial developing HO lesion but absent in mature HO. In the recurrent lesion, these PDGFRα+ 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. Stem Cells Translational Medicine 2017;6:799–806

Macrophage-derived oncostatin M contributes to human and mouse neurogenic heterotopic ossifications

“…NHOs can relapse, even 15 years after surgery (F. Genet, unpublished observations) (53), and our results indicate that NHO-MDSCs with osteogenic potential are still present in muscles after NHO resection. This hypothesis is strengthened by the recent study by Agarwal et al (54), showing that PDGFRα + MSCs are responsible for HO recurrence in a burn/tenotomy mouse model. Thus, when reactivated under specific conditions, residual NHO-MDSCs may participate in NHO recurrence.…”

Stem cells and heterotopic ossification: Lessons from animal models

“…In the current context, however, it is important to note that PDGFRα+ cells represented a small subfraction of both Mx1+ and Scx+ lineages[38]. In fact, one underlying commonality among most lineage-tracing studies that have identified contributors to intramuscular and intratendinous HO is the presence of PDGFRα+ cells (presumptive FAPs) within the heterogeneous composition of labeled cells[38,65,94,122,123]. In addition, in the burn/tendonectomy model, large aggregates of highly proliferative PDGFRα+ mesenchymal-like cells accumulated at the injury site immediately prior to the onset of HO[122,123].…”

“…In fact, one underlying commonality among most lineage-tracing studies that have identified contributors to intramuscular and intratendinous HO is the presence of PDGFRα+ cells (presumptive FAPs) within the heterogeneous composition of labeled cells[38,65,94,122,123]. In addition, in the burn/tendonectomy model, large aggregates of highly proliferative PDGFRα+ mesenchymal-like cells accumulated at the injury site immediately prior to the onset of HO[122,123]. These PDGFRα+ cells were positive for the cartilage marker SOX9, and reappeared during recurrent HO resulting from partial surgical excision of the initial HO[123].…”

“…In addition, in the burn/tendonectomy model, large aggregates of highly proliferative PDGFRα+ mesenchymal-like cells accumulated at the injury site immediately prior to the onset of HO[122,123]. These PDGFRα+ cells were positive for the cartilage marker SOX9, and reappeared during recurrent HO resulting from partial surgical excision of the initial HO[123]. Thus, cumulative data from several independent labs using diverse experimental paradigms suggest that FAP involvement may represent a common mechanistic feature of heterotopic skeletogenesis, irrespective of the proximate genetic or physical trigger.…”

Heterotopic Ossification and Hypertrophic Scars

“…However, options for prevention include non-steroidal anti-inflammatory drugs (NSAIDs) which reduce inflammation and have been used with patients after orthopedic procedures [30–36], radiation therapy which is directed to specific sites where HO may predictably form [10, 36–46], and bisphosphonates [47]. In burn patients, these preventative strategies may have more value for secondary prevention after initial excision – patients who have already undergone HO resection are at high risk for developing a second lesion or recurrence at the site of excision [48] and may be amenable to directed therapy.…”