Abstract
Although heterotopic ossification (HO) has been reported to be a common complication of the posttraumatic healing process, the underlying mechanism remains unknown. Endothelial-mesenchymal transition (EndMT) is known to play a role in HO, and our recent study observed that neuroendocrine signals can promote HO by modulating EndMT. Melatonin, a neuroendocrine hormone secreted mainly by the pineal gland, has been documented to perform its function in the skeletal system. This study aimed at describing the expression of melatonin during the formation of HO in rat models of Achilles tendon injury and to further investigate its role in regulating EndMT in HO. Histological staining revealed the expression of melatonin throughout the formation of heterotopic bone in injured Achilles tendons, and the serum melatonin levels were increased after the initial injury. Double immunofluorescence showed that the MT2 melatonin receptor was notably expressed at the sites of injury. Micro-CT showed the enhancement of heterotopic bone volume and calcified areas in rats treated with melatonin. Additionally, our data showed that melatonin induced EndMT in primary rat aortic endothelial cells (RAOECs), which acquired traits including migratory function, invasive function and EndMT and MSC marker gene and protein expression. Furthermore, our data exhibited that melatonin promoted the osteogenic differentiation of RAOECs undergoing EndMT in vitro. Importantly, inhibition of the melatonin-MT2 pathway by using the MT2 selective inhibitor 4-P-PDOT inhibited melatonin-induced EndMT and osteogenesis both in vivo and in vitro. In conclusion, these findings demonstrated that melatonin promoted HO through the regulation of EndMT in injured Achilles tendons in rats, and these findings might provide additional directions for the management of HO.
Highlights
Heterotopic ossification (HO) is a pathological process within the formation of mature bony tissues in extraskeletal sites, including joints, skeletal muscles and surrounding tissues, such as fascia and tendons (Meyers et al, 2019)
These findings demonstrate that melatonin is important for heterotopic ossification (HO) formation and that melatonin might contribute to the different stages of HO formation in injured Achilles tendons
Heterotopic bone specimens from rats with posttraumatic HO in their Achilles tendons showed the coexpression of the endothelial marker tyrosine kinase with immunoglobulin-like and EGF-like 1 (Tie-1) with the osteogenic differentiation marker OCN, suggesting that the osteoblasts in heterotopic lesions are of endothelial origin
Summary
Heterotopic ossification (HO) is a pathological process within the formation of mature bony tissues in extraskeletal sites, including joints, skeletal muscles and surrounding tissues, such as fascia and tendons (Meyers et al, 2019). HO can be conceptualized as aberrant tissue repair and is a devastating complication that is common in the healing processes of traumatic injuries, such as fractures, total hip arthroplasties, severe burns and spinal cord injuries (Li and Tuan, 2020) This pathological phenomenon is observed in a rare genetic disorder known as fibrodysplasia ossificans progressiva (FOP), which is caused by a gain-of-function mutation in the bone morphogenetic protein (BMP) type I receptor ACVR1 (Shore et al, 2006). In a rat model of Achilles tendon injury, we observed the conversion of vascular endothelial cells into MSC-like cells through BMP-4- or TGF-β2-induced EndMT (Zhang et al, 2019) These newly formed cells represented the dedifferentiation of endothelial cells into a stem cell phenotype, and cells of this phenotype can subsequently redifferentiate into osteoblasts and chondrocytes and contribute to HO formation. We confirmed the critical effect of EndMT on HO formation, illustrating the underlying regulatory mechanism of EndMT in HO formation remains challenging
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