Mesenchymal VEGFA induces aberrant differentiation in heterotopic ossification.
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ABSTRACT:
SUBMITTER: Hwang C
PROVIDER: S-EPMC6904752 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Heterotopic Ossification (HO) is the abnormal formation of ectopic bone in soft tissues generally in muscles surrounding joints such hip, knee, elbow or shoulder. The etiology of this pathology is not known but it is well established that the risk of HO is increased after traumatic brain or spinal cord injuries and also after fractures or burns. Patients with HOs suffer from pain and the range of motion from limbs with ectopic bone is highly reduced. Currently, the only effective treatment for HOs is surgical resection but they can reoccur after resection underpinning that a better understanding of its pathophysiology is required to cure patients. To date, the nature of osteogenic precursor cells (of mesenchymal origin) forming HOs is not fully elucidated and remains to be defined. A transcriptional analysis of mesenchymal stromal cells (MSCs) from HOs would help identifying molecules that could be therapeutically targeted.
2019-02-08 | GSE94683 | GEO
Project description:Heterotopic ossification (HO) is the formation of extra-skeletal bone in muscle and soft tissues. Better characterization of the signaling pathways predisposing to HO is critical to identifying therapies directed against this common and potentially debilitating condition. WISP-1 (WNT1-inducible-signaling pathway protein 1) is a CCN family member and is expressed in skeletal cells during bone development or repair. Here, we sought to comprehensively explore the significance of WISP-1 across mouse and human HO. Among CCN family members, local Wisp1 expression was most highly upregulated within experimental trauma-associated HO by RNA sequencing, and increased Wisp1 corresponded to gene markers of osteochondral differentiation. WISP1 immunolocalization demonstrated conserved expression in osteochondral cells across mouse and human HO, including an FOP-like model, post-traumatic model, and human examples of non-genetic HO. Transgenic Wisp1 global knockout demonstrated an increase in cartilage and bone in a trauma-induced HO model. Microarray and in vitro culture of Wisp1 null cells suggested that WISP1 functions as a negative regulator of chondrogenic differentiation, and that Wisp1 deletion results in unrestrained endochondral HO formation. siRNA mediated WISP1 knockdown in human progenitor cells confirmed this finding. Overall, these findings suggest that endogenous WISP1 has pathophysiologic relevance in trauma-induced HO and functions as a negative regulator of ectopic chondrogenesis.
2020-06-08 | GSE127956 | GEO
Project description:Heterotopic ossification (HO) is an aberrant regenerative process with ectopic bone induction in response to musculoskeletal trauma, in which mesenchymal stem cells (MSC) differentiate into osteochondrogenic cells instead of myocytes or tenocytes. Despite frequent cases of hospitalized musculoskeletal trauma, the inflammatory responses and cell population dynamics that regulate subsequent wound healing and tissue regeneration are still unclear. Here we examine, using a mouse model of trauma-induced HO, the local microenvironment of the initial post-injury inflammatory response. Single cell transcriptome analyses identify distinct monocyte/macrophage populations at the injury site, with their dynamic changes over time elucidated using trajectory analyses. Mechanistically, transforming growth factor beta-1 (TGFβ1)-producing monocytes/macrophages are associated with HO and aberrant chondrogenic progenitor cell differentiation, while CD47-activating peptides that reduce systemic macrophage TGFβ levels and help ameliorate HO. Our data thus implicate CD47 activation as a therapeutic approach for modulating monocyte/macrophage phenotypes, MSC differentiation and HO formation during wound healing.
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Project description:Extracellular vesicle cargo proteins shed new light on bone formation healing: Extracellular vesicle cargo proteins shed new light on bone formation
2022-04-01 | PXD030478 | Pride
Project description: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.
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Project description:Heterotopic ossification (HO) is the abnormal formation of mature bone in extraskeletal soft tissues that occurs as a result of inflammation caused by traumatic injury or associated with genetic mutation. Despite extensive research to identify the source of osteogenic progenitors, the cellular origins of HO are controversial and the underlying mechanisms, which are important for the early detection of HO, remain unclear. Here, we used in vitro and in vivo models of BMP4 and TGF-β2-induced HO to identify the cellular origin and the mechanisms mediating the formation of ectopic bone in traumatic HO. Our results suggest an endothelial origin of ectopic bone in early phase of traumatic HO and indicate that the inhibition of endothelial-mesenchymal transition by miR-630 targeting Slug plays a role in the formation of ectopic bone in HO. A matched case-control study showed that miR-630 is specifically downregulated during the early stages of HO and can be used to distinguish HO from other processes leading to bone formation. Our findings suggest a potential mechanism of post-traumatic ectopic bone formation and identify miR-630 as a potential early indicator of HO.
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Project description:Heterotopic ossification (HO) is a diverse pathologic process, defined as the formation of extraskeletal bone in muscle and soft tissues. HO can be conceptualized as a tissue repair process gone awry and is a common complication of trauma and surgery. This comprehensive review seeks to synthesize the clinical, pathoetiologic, and basic biologic features of HO, including nongenetic and genetic forms. First, the clinical features, radiographic appearance, histopathologic diagnosis, and current methods of treatment are discussed. Next, current concepts regarding the mechanistic bases for HO are discussed, including the putative cell types responsible for HO formation, the inflammatory milieu and other prerequisite "niche" factors for HO initiation and propagation, and currently available animal models for the study of HO of this common and potentially devastating condition. © 2019 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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Project description:The formation of heterotopic ossification around the shoulder is a rare but potentially debilitating condition. It is found most commonly around the hip and is usually associated with an inciting event such as trauma, burn, previous surgery, or traumatic brain/spinal cord injury. The formation of shoulder heterotopic ossification following arthroscopic surgery is very uncommon, with few data pertaining to it in the current literature. Formation of heterotopic ossification in the shoulder after arthroscopic surgery typically occurs around the acromioclavicular joint and in the subacromial space. This location may lead to chronic pain and decreased mobility. The purpose of this article is to describe an arthroscopic technique for excision of heterotopic ossification.
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Project description:Heterotopic ossification (HO, also termed myositis ossificans) is the formation of extra-skeletal bone in muscle and soft tissues. HO is a tissue repair process gone awry, and is a common complication of surgery and traumatic injury. Medical strategies to prevent and treat HO fall well short of addressing the clinical need. Better characterization of the tissues supporting HO is critical to identifying therapies directed against this common and sometimes devastating condition. The physiologic processes of osteogenesis and angiogenesis are highly coupled and interdependent. However, few efforts have been made to document the vascular patterning within heterotopic ossification. Here, surgical pathology case files of 29 human HO specimens were examined by vascular histomorphometric analysis. Results demonstrate a temporospatial patterning of HO vascularity that depends on the "maturity" of the bony lesion. In sum, human HO demonstrates a time- and space-dependent pattern of vascularization suggesting a coupled pathophysiologic process involving the coordinate processes of osteogenesis and angiogenesis. Further imaging studies may be used to further characterize vasculogenesis within HO and whether anti-angiogenic therapies are a conceivable future therapy for this common condition.
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Project description:Heterotopic ossification (HO), acquired or hereditary, endochondral or intramembranous, is the formation of true bone outside the normal skeleton. Since perivascular Gli1+ progenitors contribute to injury induced organ fibrosis, and CD133 is expressed by a variety of populations of adult stem cells, this study utilized Cre-lox based genetic lineage tracing to test the contribution to endochondral HO of adult stem/progenitor cells that expressed either Gli1 or CD133. We found that both lineages contributed broadly to different normal tissues with distinct patterns, but that only Gli1-creERT labeled stem/progenitor cells contributed to all stages of endochondral HO in a BMP dependent, injury induced, transgenic mouse model. Hedgehog (Hh) signaling was abnormal at endochondral HO lesion sites with increased signaling surrounding the lesion but diminished signaling within it. Thus, local dysregulation of Hh signaling participates in the pathophysiology of endochondral HO. However, unlike a previous report of intramembranous HO, systemic inhibition of Hh signaling was insufficient to prevent the initiation of the endochondral HO process or to treat the existing endochondral HO, suggesting that Hh participates in, but is not essential for endochondral HO in this model. This could potentially reflect the underlying difference between intramembranous and endochondral HO. Nevertheless, identification of this novel stem/precursor cell population as a HO-contributing cell population provides a potential drugable target.
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