KLF2/PPARγ axis contributes to trauma-induced heterotopic ossification by regulating mitochondrial dysfunction
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE233201 | GEO | 2023/05/29
REPOSITORIES: GEO
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Project description:Despite the high frequency of musculoskeletal extremity trauma, little is known about the dynamics of the initial inflammatory response that can result in pathologic healing. Here, we assess the circulatory monocyte/macrophage recruitment to sites of pathologic extremity wound healing as seen with heterotopic ossification (HO). Using single cell transcriptome analyses at key time points, we identify distinct monocyte/macrophage subpopulations that are recruited to the site of HO formation and contribute to ectopic bone development through varied transforming growth factor-1 (Tgfb1) expression. Monocyte/macrophage specific deletion of Tgfb1 leads to altered function of macrophages and reduced HO. We further identify CD47 as a novel target for Tgfb1 regulation on monocytes/macrophages as CD47 activation leads to decreased expression of Tgfb1 in macrophages and systemic treatment with CD47 activating peptide results in attenuation of canonical TGFB1 signaling and HO. These findings elucidate the critical role of monocytes/macrophage subpopulations in aberrant wound healing and provide a novel therapeutic avenue.
2019-10-23 | GSE126060 | GEO
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.
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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.
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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.
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Project description:Heterotopic ossification (HO) is a common, potentially debilitating, acquired pathology that is instigated by tissue damage or other insults and involves inflammation followed by chondrogenesis, osteogenesis and extraskeletal bone accumulation. Current standard of care are not very effective and have side effects, making the search for new treatments urgent. Activin A is a member of the transforming growth factor-b (TGF-b) superfamily, is produced by activated macrophages and other inflammatory cells and signals through activation of canonical SMAD2 and SMAD3 (SMAD2/3) intracellular effectors. Because HO starts with inflammation and because pSMAD2/3 activation is chondrogenic, here we tested whether activin A stimulates HO development. Using standard mouse models of acquired intramuscular and subdermal HO, we found that systemic administration of a neutralizing activin A antibody markedly reduced HO development and bone accumulation. Single-cell RNAseq and developmental trajectories showed that the antibody treatment had sharply reduced the number of Sox9+ skeletal progenitors, many of which also expressed the gene encoding activin A (Inhba), that were recruited to the HO site. In line with the latter finding, gain-of-function assays showed that treatment of progenitors with recombinant activin A enhanced their chondrogenic differentiation and did so through SMAD2/3 signaling, and inclusion of activin A to HO-inducing in vivo implants enhanced HO development. Together, our data reveal that activin A is a critical upstream signaling stimulator of HO in mice and could represent an effective therapeutic target against acquired forms of this pathology in patients.
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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.
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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.
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Project description:We have reported that loss of Tnmd leads to inferior early tendon repair characterized by fibrovascular scaring and therefore hypothesized that its lack will persistently cause deficient repair during later stages. Tnmd knockout (Tnmd-/-) and wild-type (WT) animals were subjected to complete Achilles tendon surgical transection followed by end-to-end suture. Lineage tracing revealed a reduction in tendon-lineage cells marked by ScleraxisGFP, but an increase in alpha smooth muscle actin myofibroblasts in Tnmd-/- tendon scars. At the proliferative stage, more pro-inflammatory M1 macrophages and larger collagen II cartilaginous template were detected in this group. At the remodeling stage, histological scoring revealed lower repair quality in the injured Tnmd-/- tendons, which was coupled with higher HO quantified by micro-CT. Tendon biomechanical properties were compromised in both groups upon injury, however we identified an abnormal stiffening of non-injured Tnmd-/- tendons, which possessed higher static and dynamic E-moduli. Pathologically thicker and abnormally shaped collagen fibrils were observed by TEM in Tnmd-/- tendons and this together with augmented HO resulted in diminished running capacity of Tnmd-/- mice. These novel findings demonstrate that Tnmd plays a protecting role against trauma-induced endochondral HO and can inspire the generation of novel therapeutics to accelerate repair.
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Project description:Heterotopic ossification (HO) occurs following mechanical trauma, burns, or congenitally in patients suffering from fibrodysplasia ossificans progressiva (FOP). Recently, we demonstrated that inhibitors of phosphatidyl-inositol 3-kinase alpha (PI3Kα), including the already marketed BYL719/Alpelisib/Piqray, may become a useful therapy for patients undergoing HO. In this study, we have confirmed these results and optimized the timing of administration of BYL719. We found that BYL719 effectively prevents HO when administered even up to three to seven days after injury. We demonstrate in cell cultures and in a mouse model of HO, that the major actions of BYL719 are on-target effects through inhibition of PI3Kα, without directly affecting ACVR1/ALK2 kinase activity. In vivo, we found that lack of PI3Kα in progenitors at injury sites is sufficient to prevent HO. Moreover, time course assays in HO lesions demonstrate that BYL719 not only blocks osteochondroprogenitor specification, but also reduces the inflammatory response. BYL719 inhibits the migration, the proliferation, and the expression of pro-inflammatory cytokines in monocytes and mast cells, suggesting that BYL719 hampers the hyper-inflammatory status of HO lesions. As part of this study, we have conducted bulk RNA sequencing using human mesenchymal stem cells (hMSCs) expressing ACVR1/ALK2-R206H to assess molecular effectors driving the therapeutic potential of BYL719 in FOP. Altogether, these results highlight the potential of PI3Kα inhibition as a safe and effective therapeutic strategy for HO.
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