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

Shailesh Agarwal,Shawn Loder,Shuli Li,John Li,Cameron Brownley,Benjamin Levi,Joshua Peterson,David Cholok,Chris Breuler,James Drake

doi:10.5966/sctm.2015-0365

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

Highlights

Trauma-induced heterotopic ossification (HO) is the pathologic formation of extraskeletal bone that occurs after severe musculoskeletal injuries or orthopedic operations such as total hip arthroplasty (THA) [1,2,3,4]
Upon confirming that key mediators of initial HO development are absent after 9 weeks, we set out to create a model of HO recurrence
We found that the initial HO lesion could be excised surgically, albeit incompletely, based on pre- and immediate postexcision microCT imaging (Fig. 2B, 2C)

Summary

Introduction

Trauma-induced heterotopic ossification (HO) is the pathologic formation of extraskeletal bone that occurs after severe musculoskeletal injuries or orthopedic operations such as total hip arthroplasty (THA) [1,2,3,4]. The incidence of HO in secondary THAs is nearly four times that of primary operations. HO insidiously develops in patients months after the inciting traumatic event. Patients may complain of chronic pain, the sensation of a bony prominence, loss of muscle or joint excursion, and even open wounds. When patients have these signs or symptoms, plain-film radiographs or computed tomography (CT) imaging can elucidate the underlying cause. Therapeutics targeted at HO are being investigated for their ability to prevent or mitigate the key signaling processes involved in the development of cartilage or subsequent

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Conclusion