Direct Mouse Trauma/Burn Model of Heterotopic Ossification

Abstract

Heterotopic ossification (HO) is the formation of bone outside of the skeleton which forms following major trauma, burn injuries, and orthopaedic surgical procedures. The majority of animal models used to study HO rely on the application of exogenous substances, such as bone morphogenetic protein (BMP), exogenous cell constructs, or genetic mutations in BMP signaling. While these models are useful they do not accurately reproduce the inflammatory states that cause the majority of cases of HO. Here we describe a burn/tenotomy model in mice that reliably produces focused HO. This protocol involves creating a 30% total body surface area partial thickness contact burn on the dorsal skin as well as division of the Achilles tendon at its midpoint. Relying solely on traumatic injury to induce HO at a predictable location allows for time-course study of endochondral heterotopic bone formation from intrinsic physiologic processes and environment only. This method could prove instrumental in understanding the inflammatory and osteogenic pathways involved in trauma-induced HO. Furthermore, because HO develops in a predictable location and time-course in this model, it allows for research to improve early imaging strategies and treatment modalities to prevent HO formation.

SMAD7 prevents heterotopic ossification in a rat Achilles tendon injury model via regulation of endothelial–mesenchymal transition

“…To date, the majority of animal models used for studying HO involve the application of BMP, genetic mutations in the BMP signalling or collagenase‐induced tendinopathy . More recently, Achilles tenotomy is performed with a dorsal partial burn injury .…”

Cellular Plasticity in Musculoskeletal Development, Regeneration, and Disease

“…As it has been observed that transection of the Achilles’ tendon in mice can lead to HO, tendon cells have also been investigated as possible progenitor cells. Using the tendon specific marker, Scleraxis (Scx), Howell et al noted that Scx‐lineage traced cells gave rise to cartilage following tenectomy while Agarwal et al showed that Scx‐Cre cells contribute to all phases of HO in a burn/tenectomy model .…”

Tendon mineralization is progressive and associated with deterioration of tendon biomechanical properties, and requires BMP-Smad signaling in the mouse Achilles tendon injury model

“…(O'Brien et al, 2012;Fenwick et al, 2002;Agabalyan et al, 2013;Hatori et al, 2002). It has been shown that transection of Achilles tendons (Tenosectomy) in rodents induces ectopic mineralization via endochondral ossification (Rooney et al, 1992;Lin et al, 2010;Peterson et al, 2015). Using a murine model, we recently demonstrated that tendon progenitor-like cells appear in injured tendons, have strong chondrogenic potential, and may contribute to ectopic mineralization (Asai et al, 2014).…”