Abstract
Despite the fact that extensive studies have focused on heterotopic ossification (HO), its molecular mechanism remains unclear. The endothelial‐mesenchymal transition (EndMT), which may be partially modulated by neuroendocrine cytokines is thought to play a major role in HO. Neurotrophin‐3 (NT‐3), which has neuroendocrine characteristics is believed to promote skeletal remodeling. Herein, we suggest that that NT‐3 may promote HO formation through regulation of EndMT. Here, we used an in vivo model of HO and an in vitro model of EndMT induction to elucidate the effect and underlying mechanism of NT‐3 on EndMT in HO. Our results showed that heterotopic bone and cartilage arose from EndMT and NT‐3 promoted HO formation in vivo. Our in vitro results showed that NT‐3 up‐regulated mesenchymal markers (FSP‐1, α‐SMA and N‐cadherin) and mesenchymal stem cell (MSC) markers (STRO‐1, CD44 and CD90) and down‐regulated endothelial markers (Tie‐1, VE‐cadherin and CD31). Moreover, NT‐3 enhanced a chondrogenesis marker (Sox9) and osteogenesis markers (OCN and Runx2) via activation of EndMT. However, both EndMT specific inhibitor and tropomyosin‐related kinase C (TrkC) specific inhibitor rescued NT‐3‐induced HO formation and EndMT induction in vivo and in vitro. In conclusion, our findings demonstrate that NT‐3 promotes HO formation via modulation of EndMT both in vivo and in vitro, which offers a new potential target for the prevention and therapy of HO.
Highlights
heterotopic ossification (HO), characterized as ectopic bone formation in extraskeletal soft tissues is usually acquired after injuries and rarely derives from ge‐ netic mutations, such as fibrodysplasia ossificans progressive (FOP).[1]
Recent studies have revealed that endothelial‐mesenchymal transition (EndMT) was induced in response to constitutive bone morphogenetic protein (BMP) signalling in animal models representing a dedifferentiation of endothelial cells to a mesenchymal stem‐like phenotype, which can subsequently redifferentiate into various cell lineages.[9,23,28]
Previous studies have found that ectopic bone and cartilage cells express endothelial markers in a model of BMP‐4 and transforming growth factor (TGF)‐β2‐induced HO, which suggests that heterotopic bone and cartilage formation arises from endothelial cells.[9,11]
Summary
HO, characterized as ectopic bone formation in extraskeletal soft tissues is usually acquired after injuries and rarely derives from ge‐ netic mutations, such as fibrodysplasia ossificans progressive (FOP).[1]. The cellular origin of ec‐ topic bone in HO remains controversial.[5] Previous studies observed that tissue injuries induced local MSCs to differentiate into bone in HO, which suggests that MSC dysregulation serves as a common. We demonstrated that the formation of heterotopic cartilage and bone is caused by EndMT and suggested a potential mechanism that NT‐3 can promote the formation of HO through induction of EndMT both in vivo and in vitro
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