Wisp inhibits chondrogenic differentiation in heterotopic ossification
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ABSTRACT:
PROVIDER: PRJNA525862 | ENA |
REPOSITORIES: ENA
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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:Trauma-induced heterotopic ossification (HO) is one of the most complex disorders after musculoskeletal injury and is characterized by aberrant extraskeletal bone formation. Recent studies have shed light on the critical role of dysregulated osteogenic differentiation in aberrant bone formation. Krupel-like factor 2 (KLF2) and peroxisome proliferator-activated receptor gamma (PPARγ) are master adapter proteins that link cellular responses to osteogenesis; however, their roles and relationships in HO remain elusive.
2023-05-29 | GSE233201 | GEO
Project description:Tenomodulin prevents trauma-induced heterotopic ossification in tendon
| PRJNA743873 | ENA
Project description:The mechanism of heterotopic ossification remains largely unclarified. in this project, we administrated Achilles tenotomy (AT) and partial Achilles tenotomy (PAT) to rat models to simulate the varied size of ectopic bone we observed in the clinical courses. Then we applied Data-independent acquisition (DIA) proteomic strategy to identify the proteins and signaling pathways associated with the progress of heterotopic ossification and propagation of the ectopic bone mass.
2021-04-28 | PXD025678 | iProX
Project description:Heterotopic ossification (HO) consists of extraskeletal bone formation. One form of HO is acquired and instigated by traumas or surgery, and another form is genetic and characterizes Fibrodysplasia Ossificans Progressiva (FOP). We and others showed that activin A promotes both acquired and genetic HO and found that the retinoid agonist Palovarotene inhibits both HO forms in mice. We asked whether Palovarotene's action against HO may include an interference with endogenous activin A expression and/or function. Using a mouse model of acquired HO, we found that activin A and its encoding RNA (Inhba) were prominent in chondrogenic cells within developing HO masses in untreated mice. Single cell RNAseq (scRNAseq) assays verified that Inhba expression characterized chondroprogenitors and chondrocytes in untreated HO, in addition to its expected expression in inflammatory cells and macrophages. Palovarotene administration caused a sharp inhibition of both HO and amounts of activin A and Inhba transcripts. Bioinformatic analyses of scRNAseq datasets indicated that the drug had reduced interactions and crosstalk amongst cell populations. Our data reveal that Palovarotene markedly reduces the number of local Inhba-expressing HO-forming populations.
2023-07-01 | GSE233843 | GEO
Project description:To investigate whether circRNAs could participate in the pathological osteogenesis of traumatic heterotopic ossification (HO). RNA sequencing was performed to analyze the circRNA expression profile in mice HO tissues and to investigate the relevant mechanisms. We found that 491 circRNAs were significantly differentially expressed in mouse HO tissues by a fold-change ≥2 and p-value ≤0.05. Among these, 168 circRNAs were upregulated, while 323 were downregulated.
2022-11-05 | GSE217301 | GEO
Project description:Heterotopic ossification (HO), the pathologic growth of extra-skeletal bone, occurs as a common complication of trauma or in genetic disorders and can be disabling and lethal.We report that mice harboring injury-induced HO exhibit bone loss similar to the presentation of HO patients. Esepecially, Fetuin A dysregulation promotes immunosupression in HO lesion to link HO and bone loss.
2022-11-02 | GSE161388 | GEO
Project description:Mutations in the RMRP gene are the origin of cartilage-hair hypoplasia. Cartilage-hair hypoplasia is associated with severe dwarfism caused by impaired skeletal development. However, it is not clear why mutations in the RMRP gene lead to skeletal dysplasia. Viperin is a known substrate of RMRP. Since chondrogenic differentiation of the growth plate is required for development of the long bones, we hypothesized that viperin functions as a chondrogenic regulator downstream of RMRP. Viperin protein is expressed throughout the stages of chondrogenic differentiation in vivo. Viperin gene expression is increased during knockdown of Rmrp RNA in the ATDC5 model for chondrogenic differentiation. Viperin is expressed during ATDC5 chondrogenic differentiation. Viperin knockdown reduces, while viperin overexpression increases overall protein secretion, with CXCL10 identified as a potential target via mass spectrometry-proteomics. CXCL10 protein expression is reduced during knockdown and increased during overexpression of viperin and CXCL10 protein expression coincides with viperin expression in ATDC5 chondrogenic differentiation. Viperin knockdown induces, while viperin overexpression reduces TGFβ activity. Furthermore, viperin knockdown conditioned media increases, while viperin overexpression conditioned media reduces chondrogenic differentiation of ATDC5 cells. TGFβ target genes Pai1 and Smad7 are increased during knockdown and reduced during overexpression of viperin. Moreover, TGFβ activity is reduced when differentiating ATDC5 cells are exposed to CXCL10 and, acting as a viperin overexpression mimic, CXCL10 similarly reduces chondrogenic differentiation of ATDC5. Lastly, we show that in CHH patient cells, RMRP expression is reduced and viperin expression is increased, coinciding with reduced chondrogenic differentiation and increased CXCL10 expression, possibly explaining the CHH phenotype. Together our data show that viperin may play a pivotal role in chondrogenic differentiation, with potential consequences for cartilage-hair hypoplasia pathobiology.
2019-02-15 | PXD006999 | Pride
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:Brain-derived extracellular vesicles participate in inter-organ communication after traumatic brain injury by transporting pathogens to initiate secondary injury. Inflammasome related proteins encapsulated in brain-derived extracellular vesicles are capable of crossing the blood-brain barrier to reach distal tissues. These proteins initiate inflammatory dysfunction such as neurogenic heterotopic ossification. This recurrent condition is highly debilitating to patients because of its relatively unknown pathogenesis and the lack of effective prophylactic intervention strategies. Accordingly, a rat model of neurogenic heterotopic ossification that combined traumatic brain injury and achillotenotomy was developed to address these two issues. Histological examination of the injured tendon identified the coexistence of ectopic calcification and fibroblast pyroptosis. The relationships among brain-derived extracellular vesicles, fibroblast pyroptosis and ectopic calcification were further investigated in vitro and in vivo. Intravenous injection of the pyroptosis inhibitor Ac-YVAD-cmk reversed the development of neurogenic heterotopic ossification in vivo. The present work highlighted the role of brain-derived extracellular vesicles in the pathogenesis of neurogenic heterotopic ossification and offered a potential strategy for the prevention of neurogenic heterotopic ossification after traumatic brain injury.
2023-11-02 | PXD046626 | iProX