A novel mouse model of trauma induced heterotopic ossification

Abstract

Severe soft tissue trauma is associated with heterotopic ossification (HO), the abnormal deposition of bone at extraskeletal sites. The pathophysiology of the development of trauma-induced HO remains largely unknown due in part to the lack of appropriate animal models. In this study, we sought to develop a new trauma-induced HO mouse model using muscle impact injury combined with low dose BMP-2. BMP-2 at doses ranging from 0 to 2 mg was injected into quadriceps muscles of adult male C57/BL6 mice. Animals then received a one-time quadriceps impaction injury to mimic the trauma associated with severe injuries. HO was monitored using in vivo microCT scanning at 1, 2, 4, and 8 weeks after treatment. After trauma, the expression of BMP-2, -4, BMP receptor 1, SOX9 and RUNX2 were increased in muscle. Although little or no HO was observed in mice receiving 1 mg BMP-2, combining this dose with muscle trauma produced an abundance of HO. At higher doses of BMP-2, trauma did not augment mineral deposition. These results suggest that BMP-2 signaling can sensitize muscle to trauma-induced HO. They also provide the basis for a new model to study the pathogenesis of trauma-induced HO. ß

Early Detection of Heterotopic Ossification for Effective Prevention and Treatment

“…On the other hand, bone injury (osteotomy) alone or in combination with muscle injury increased the proportion of muscle-derived MSCs in the total population of M-MSCs and the osteogenic potential of M-MSCs. This is consistent with a recently published study, in which muscle injury alone failed to induce HO [35] . But muscle injury and the application of a low dose of BMP-2 (bone morphogenetic protein-2), which could not induce ossification alone, induced robust HO.…”

Novel mouse model of spinal cord injury-induced heterotopic ossification

“…Third, we only evaluated HO BV at a single time point-2 wk after BMP-2 injection in this study. This time point was chosen based on the time course of BMP-2-induced HO we tested in C57/BL6 mice previously [16], in which we found that HO develops no later than 2 wk after BMP-2 injection. However, the mice we used for the previous time course study did not receive surgeries.…”

“…Previous studies have shown that bone morphogenetic proteins (BMPs) can sufficiently induce HO in mice [15]. Based on this finding, we have recently developed a mouse model of trauma-induced HO by combining intramuscular injection of a small dose of BMP-2 with focal muscle injury [16]. However, this model does not include an SCI component.…”

An In Vitro Model for the Development of Mature Bone Containing an Osteocyte Network

“…There are also several modalities to recreate pathological ossifications in animal models, including the overexpression or inhibition of mole cular osteoinductive factors, trauma induction, and heterotopic implantation. [16][17][18] However, some of these models are not fully representative of the pathological states, requiring the use of a large number of animals; or are too complex to allow the isolation of individual contributing factors in early phase bone formation, which makes it objectively difficult to answer some essential questions on biological ossification. [16] Developing novel ways to produce ossified tissue is essential for several scientific reasons.…”

“…[16][17][18] However, some of these models are not fully representative of the pathological states, requiring the use of a large number of animals; or are too complex to allow the isolation of individual contributing factors in early phase bone formation, which makes it objectively difficult to answer some essential questions on biological ossification. [16] Developing novel ways to produce ossified tissue is essential for several scientific reasons. From a biological perspective, new models will help to develop a deeper understanding of the fundamental processes underlying both early bone development and the pathological ossification events following trauma or injury.…”