Stem cells and heterotopic ossification: Lessons from animal models

Abstract

Put most simply, heterotopic ossification (HO) is the abnormal formation of bone at extraskeletal sites. HO can be classified into two main subtypes, genetic and acquired. Acquired HO is a common complication of major connective tissue injury, traumatic central nervous system injury, and surgical interventions, where it can cause significant pain and postoperative disability. A particularly devastating form of HO is manifested in the rare genetic disorder, fibrodysplasia ossificans progressiva (FOP), in which progressive heterotopic bone formation occurs throughout life, resulting in painful and disabling cumulative immobility. While the central role of stem/progenitor cell populations in HO is firmly established, the identity of the offending cell type(s) remains to be conclusively determined, and little is known of the mechanisms that direct these progenitor cells to initiate cartilage and bone formation. In this review, we summarize current knowledge of the cells responsible for acquired HO and FOP, highlighting the strengths and weaknesses of animal models used to interrogate the cellular origins of HO.

In vivo dynamic analysis of BMP-2-induced ectopic bone formation

“…In vivo quantitative analysis of how and when pharmacological agents that affect ectopic bone formation can facilitate the optimization of this process is lacking. Studies are underway to elucidate the controversial origin of the OBs that contribute to ectopic bone formation using intravital imaging of ectopic bone formation 39 .…”

Neurotrophin‐3 acts on the endothelial‐mesenchymal transition of heterotopic ossification in rats

“…All animal experimental protocols were approved by the Ethics Committee for Animal Research of Southern Medical University. Ninety‐six Sprague Dawley (SD) rats (6‐week‐old and regardless of gender) were purchased from the Laboratory Animal Center of Southern Medical University and subjected to an Achilles tenotomy using a posterior midpoint approach under aseptic conditions to induce HO . For gene expression and histological analysis of NT‐3, rats were killed at 4, 8 and 12 weeks after surgery (n = 6/time point); a control group was also killed (n = 6).…”

“…Ninety-six Sprague Dawley (SD) rats (6-week-old and regardless of gender) were purchased from the Laboratory Animal Center of Southern Medical University and subjected to an Achilles tenotomy using a posterior midpoint approach under aseptic conditions to induce HO. 21 For gene expression and histological analysis of NT-3, rats were killed at 4, 8 and 12 weeks after surgery (n = 6/ time point); a control group was also killed (n = 6). For the EndMT study, 24 injured rats were randomly divided into four groups (n = 6/group): three groups received a sub-cutaneous injection of recombinant NT-3, BMP-4 or TGF-β2 (1.2 mg/mL, receiving 12 mg injection per week) (R&D Systems, Minneapolis, MN, USA) once a week surrounding the Achilles tendon.…”

Challenges of heterotopic ossification—Molecular background and current treatment strategies

“…These differentiation pathways depend on signals from the local microenvironment . Recent data have demonstrated the regenerative potential of mesenchymal progenitor cells (MPSs) in traumatically injured muscle and, based on their osteogenic properties, suggest these cells play a role in HO formation . However, there is still considerable debate about the cellular origins of HO.…”

“…Many recent papers suggest that the heterogeneity of cell origin thought to be responsible for HO could be due to the variation in the investigative models . Several critical elements, such as progenitor cell populations, inductive factors, and a favourable environment, may contribute to HO . It is well known that the differentiation of progenitor cells toward a chondrogenic lineage and endochondral ossification is promoted by diverse factors, including BMP signalling, transcription factors such as SOX, and hypoxic conditions.…”