Enpp1 inhibits ectopic joint calcification and maintains articular chondrocytes by repressing hedgehog signaling.
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ABSTRACT:
SUBMITTER: Jin Y
PROVIDER: S-EPMC6176935 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Generalized arterial calcification of infancy (GACI) is a rare disorder caused by ENPP1 or ABCC6 variants. GACI is characterized by low pyrophosphate, arterial calcification, and high mortality during the first year of life, but the natural course and possible differences between the causative genes remain unknown. In all, 247 individual records for patients with GACI (from birth to 58.3 years of age) across 19 countries were reviewed. Overall mortality was 54.7% (13.4% in utero or stillborn), with a 50.4% probability of death before the age of 6 months (critical period). Contrary to previous publications, we found that bisphosphonate treatment had no survival benefit based on a start-time matched analysis and inconclusive results when initiated within 2 weeks of birth. Despite a similar prevalence of GACI phenotypes between ENPP1 and ABCC6 deficiencies, including arterial calcification (77.2% and 89.5%, respectively), organ calcification (65.8% and 84.2%, respectively), and cardiovascular complications (58.4% and 78.9%, respectively), mortality was higher for ENPP1 versus ABCC6 variants (40.5% versus 10.5%, respectively; p = 0.0157). Higher prevalence of rickets was reported in 70.8% of surviving affected individuals with ENPP1 compared with that of ABCC6 (11.8%; p = 0.0001). Eleven affected individuals presenting with rickets and without a GACI diagnosis, termed autosomal recessive hypophosphatemic rickets type 2 (ARHR2), all had confirmed ENPP1 variants. Approximately 70% of these patients demonstrated evidence of ectopic calcification or complications similar to those seen in individuals with GACI, which shows that ARHR2 is not a distinct condition from GACI but represents part of the spectrum of ENPP1 deficiency. Overall, this study identified an early mortality risk in GACI patients despite attempts to treat with bisphosphonates, high prevalence of rickets almost exclusive to ENPP1 deficiency, and a spectrum of heterogenous calcification and multiple organ complications with both ENPP1 and ABCC6 variants, which suggests an overlapping pathology. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.
| S-EPMC8595532 | biostudies-literature
Project description:Sonic hedgehog (Shh) is involved in the induction of early cartilaginous differentiation of mesenchymal cells in the limb. We investigated whether Shh could promote redifferentiation of dedifferentiated chondrocytes and have a favorable effect on the regeneration of cartilage. Articular chondrocytes of rats were separated and cultured. The redifferentiation of dedifferentiated chondrocytes transfected with Shh was evaluated using monolayer and pellet culture system. The signaling molecules (Ptc 1, Gli 1 and Sox9) of the hedgehog pathway were investigated. A rat model of articular cartilage defect was used to evaluate cartilage repair after transplantation with dedifferentiated chondrocytes. After Shh gene transfer, the hedgehog pathway was upregulated in dedifferentiated chondrocytes. Real time-PCR and western blot analysis verified the stronger expression of Ptc1, Gli1 and Sox9 in Shh transfected cells. Shh upregulates the Shh signaling pathway and multiple cytokines (bone morphogenetic protein 2 and insulin-like growth factor 1) in dedifferentiated chondrocytes. After transplantation in the joint, histologic analysis of the regenerative tissues revealed that significantly better cartilage repair in rats transplanted with Shh transfected cells. These data suggest that Shh could induce redifferentiation of dedifferentiated chondrocytes through up-regulating Shh signaling pathway, and have considerable therapeutic potential in cartilage repair.
| S-EPMC3922882 | biostudies-literature
Project description:Disease can alter natural ramp-like elastic gradients to steeper step-like profiles at soft-hard tissue interfaces. Prolonged function can further mediate mechanochemical events that alter biomechanical response within diseased organs. In this study, a human bone-tooth fibrous joint was chosen as a model system, in which the effects of bacterial-induced disease, i.e. periodontitis, on natural elastic gradients were investigated. Specifically, the effects of ectopic biomineral, i.e. calculus, on innate chemical and elastic gradients within the cementum-dentin complex, both of which are fundamental parameters to load-bearing tissues, are investigated through comparisons with a healthy complex. Complementary techniques for mapping changes in physicochemical properties as a result of disease included micro X-ray computed tomography, microprobe micro X-ray fluorescence imaging, transmission electron and atomic force microscopy (AFM) techniques, and AFM-based nanoindentation. Results demonstrated primary effects as derivatives of ectopic mineralization within the diseased fibrous joint. Ectopic mineralization with no cementum resorption, but altered cementum physicochemical properties with increasing X-ray attenuation, exhibited stratified concretion with increasing X-ray fluorescence counts of calcium and phosphorus elements in the extracellular matrix in correlation with decreased hygroscopicity, indenter displacement, and apparent strain-relieving characteristics. Disease progression, identified as concretion through the periodontal ligament (PDL)-cementum enthesis, and sometimes the originally hygroscopic cementum-dentin junction, resulted in a significantly increased indentation elastic modulus (3.16±1.19 GPa) and a shift towards a discontinuous interface compared with healthy conditions (1.54±0.83 GPa) (Student's t-test, P<0.05). The observed primary effects could result in secondary downstream effects, such as compromised mechanobiology at the mechanically active PDL-cementum enthesis that can catalyze progression of disease.
| S-EPMC3529509 | biostudies-literature
Project description:The goal of this study was to identify new mutations in the ENPP1 gene that produce infantile arterial calcification and fetal demise. A stillborn (proband) was diagnosed with infantile arterial calcification. Mutations in the ENPP1 gene account for ~80% of the cases of infantile arterial calcification through loss of function in both alleles (recessive inheritance).
2011-01-26 | GSE26860 | GEO
Project description:ObjectiveNotch signaling has been identified as a critical regulator in cartilage development and joint maintenance, and loss of Notch signaling in all joint tissues results in an early and progressive osteoarthritis (OA)-like pathology. This study investigated the targeted cell population within the knee joint in which Notch signaling is required for normal cartilage and joint integrity.MethodsTwo loss-of-function mouse models were generated with tissue-specific knockout of the core Notch signaling component, RBPjκ. The AcanCre(ERT2) transgene specifically removed Rbpjκ floxed alleles in postnatal joint chondrocytes, while the Col1Cre(2.3kb) transgene deleted Rbpjκ in osteoblast populations, including subchondral osteoblasts. Mutant and control mice were analyzed via histology, immunohistochemistry (IHC), real-time quantitative polymerase chain reaction (qPCR), X-ray, and microCT imaging at multiple time-points.ResultsLoss of Notch signaling in postnatal joint chondrocytes results in a progressive OA-like pathology, and triggered the recruitment of non-targeted fibrotic cells into the articular cartilage potentially due to mis-regulated chemokine expression from within the cartilage. Upon recruitment, these fibrotic cells produced degenerative enzymes that may lead to the observed cartilage degradation and contribute to a significant portion of the age-related OA-like pathology. On the contrary, loss of Notch signaling in subchondral osteoblasts did not affect normal cartilage development or joint maintenance.ConclusionsRBPjκ-dependent Notch signaling in postnatal joint chondrocytes, but not subchondral osteoblasts, is required for articular cartilage and joint maintenance.
| S-EPMC4799757 | biostudies-literature
Project description:A switch from autophagy to apoptosis is implicated in chondrocytes during the osteoarthritis (OA) progression with currently unknown mechanism(s). In this study we utilized a flow fluid shear stress (FFSS) model in cultured chondrocytes and a unilateral anterior crossbite (UAC) animal model. We found that both FFSS and UAC actively induced endoplasmic reticulum stress (ERS) in the temporomandibular joints (TMJ) chondrocytes, as demonstrated by dramatic increases in expression of HSPA5, p-EIF2AK3, p-ERN1 and ATF6. Interestingly, both FFSS and UAC activated not only pro-death p-EIF2AK3-mediated ERS-apoptosis programs but also pro-survival p-ERN1-mediated autophagic flux in chondrocytes. Data from FFSS demonstrated that MTORC1, a downstream of p-ERN1, suppressed autophagy but promoted p-EIF2AK3 mediated ERS-apoptosis. Data from UAC model demonstrated that at early stage both the p-ERN1 and p-EIF2AK3 were activated and MTORC1 was inhibited in TMJ chondrocytes. At late stage, MTORC1-p-EIF2AK3-mediated ERS apoptosis were predominant, while p-ERN1 and autophagic flux were inhibited. Inhibition of MTORC1 by TMJ local injection of rapamycin in rats or inducible ablation of MTORC1 expression selectively in chondrocytes in mice promoted chondrocyte autophagy and suppressed apoptosis, and reduced TMJ cartilage loss induced by UAC. In contrast, MTORC1 activation by TMJ local administration of MHY1485 or genetic deletion of Tsc1, an upstream MTORC1 suppressor, resulted in opposite effects. Collectively, our results establish that aberrant mechanical loading causes cartilage degeneration by activating, at least in part, the MTORC1 signaling which modulates the autophagy and apoptosis programs in TMJ chondrocytes. Thus, inhibition of MTORC1 provides a novel therapeutic strategy for prevention and treatment of OA.Abbreviations : ACTB: actin beta; ATF6: activating transcription factor 6; BECN1: beclin 1; BFL: bafilomycin A1; CASP12: caspase 12; CASP3: caspase 3; DAPI: 4',6-diamidino-2-phenylindole; DDIT3: DNA-damage inducible transcript 3; EIF2AK3/PERK: eukaryotic translation initiation factor 2 alpha kinase 3; ER: endoplasmic reticulum; ERS: endoplasmic reticulum stress; ERN1/IRE1: endoplasmic reticulum to nucleus signaling 1; FFSS: flow fluid shear stress; HSPA5/GRP78/BiP: heat shock protein 5; LAMP2: lysosome-associated membrane protein 2; MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin complex 1; OA: osteoarthritis; PRKAA1/2/AMPK1/2: protein kinase, AMP-activated, alpha 1/2 catalytic subunit; RPS6: ribosomal protein S6; Rapa: rapamycin; SQSTM1/p62: sequestosome 1; TEM: transmission electron microscopy; TG: thapsigargin; TMJ: temporomandibular joints; TSC1/2: tuberous sclerosis complex 1/2; UAC: unilateral anterior crossbite; UPR: unfolded protein response; XBP1: x-box binding protein 1.
| S-EPMC6984599 | biostudies-literature
Project description:Both the WNT/?-catenin and hedgehog signaling pathways are important in the regulation of limb development, chondrocyte differentiation, and degeneration of articular cartilage in osteoarthritis (OA). It is not clear how these signaling pathways interact in interzone cell differentiation and synovial joint morphogenesis. Here, we determined that constitutive activation of hedgehog signaling specifically within interzone cells induces joint morphological changes by selectively inhibiting ?-catenin-induced Fgf18 expression. Stabilization of ?-catenin or treatment with FGF18 rescued hedgehog-induced phenotypes. Hedgehog signaling induced expression of a dominant negative isoform of TCF7L2 (dnTCF7L2) in interzone progeny, which may account for the selective regulation of ?-catenin target genes observed. Knockdown of TCF7L2 isoforms in mouse chondrocytes rescued hedgehog signaling-induced Fgf18 downregulation, while overexpression of the human dnTCF7L2 orthologue (dnTCF4) in human chondrocytes promoted the expression of catabolic enzymes associated with OA. Similarly, expression of dnTCF4 in human chondrocytes positively correlated with the aggrecanase ADAMTS4. Consistent with our developmental findings, activation of ?-catenin also attenuated hedgehog-induced or surgically induced articular cartilage degeneration in mouse models of OA. Thus, our results demonstrate that hedgehog inhibits selective ?-catenin target gene expression to direct interzone progeny fates and articular cartilage development and disease. Moreover, agents that increase ?-catenin activity have the potential to therapeutically attenuate articular cartilage degeneration as part of OA.
| S-EPMC4855923 | biostudies-literature
Project description:BackgroundPrevious studies showed that doxorubicin could lead to osteoarthritis (OA) by inducing chondrocyte inflammation and apoptosis. Besides, it is reported that platelet-rich plasma (PRP) could suppress the activation of inflammatory NF-κB signaling. Here, we aimed to determine whether PRP was able to exert a protective effect against doxorubicin-induced chondrocyte damages.MethodsTo determine whether PRP protects chondrocytes against destabilization of the medial meniscus (DMM)-induced osteoarthritis, mice were treated with PRP and doxorubicin, and the cartilage destruction was observed through Safranin O-fast green staining and osteoarthritis scoring. ELISA assay was used to check the release of TNF-α and ILs. In vitro, we treated chondrocytes with doxorubicin and PRP; CCK-8 was used to measure cell viability. Western blot, real-time PCR, and ELISA were applied to check apoptosis-related signaling and inflammation-associated factors.ResultsThe results from the mouse model suggested that PRP attenuated doxorubicin-induced cartilage destruction in vivo. Doxorubicin promoted chondrocyte apoptosis while PRP ameliorated this damage. PRP inhibited doxorubicin-induced dysregulation of cell matrix-related factors, including SOX9, Col2A1, Col10A1, and Aggrecan, reduced protein levels of doxorubicin-induced inflammatory markers, COX-2, and iNOS, and blocked doxorubicin-induced phosphorylation of IκB and NF-κB in articular chondrocytes.ConclusionsPRP improved doxorubicin-induced damage on chondrocytes. This research might provide a new theoretical basis for the clinical treatment of osteoarthritis caused by doxorubicin.
| S-EPMC8229346 | biostudies-literature
Project description:Adult articular chondrocytes lack an effective repair response to correct damage from injury or osteoarthritis. Polypeptide growth factors that stimulate articular chondrocyte proliferation and cartilage matrix synthesis may augment this response. Gene transfer is a promising approach to delivering such factors. Multiple growth factor genes regulate these cell functions, but multiple growth factor gene transfer remains unexplored. We tested the hypothesis that multiple growth factor gene transfer selectively modulates articular chondrocyte proliferation and matrix synthesis. We tested the hypothesis by delivering combinations of the transgenes encoding insulin-like growth factor I (IGF-I), fibroblast growth factor-2 (FGF-2), transforming growth factor beta1 (TGF-?1), bone morphogenetic protein-2 (BMP-2), and bone morphogenetic protien-7 (BMP-7) to articular chondrocytes and measured changes in the production of DNA, glycosaminoglycan, and collagen. The transgenes differentially regulated all these chondrocyte activities. In concert, the transgenes interacted to generate widely divergent responses from the cells. These interactions ranged from inhibitory to synergistic. The transgene pair encoding IGF-I and FGF-2 maximized cell proliferation. The three-transgene group encoding IGF-I, BMP-2, and BMP-7 maximized matrix production and also optimized the balance between cell proliferation and matrix production. These data demonstrate an approach to articular chondrocyte regulation that may be tailored to stimulate specific cell functions, and suggest that certain growth factor gene combinations have potential value for cell-based articular cartilage repair.
| S-EPMC3994886 | biostudies-literature
Project description:Osteoarthritic (OA) chondrocytes are shown to express inducible nitric oxide synthase (iNOS) which produces high concentrations of nitric oxide (NO), particularly when stimulated with proinflammatory cytokines. NO is involved in OA cartilage degradation. On the other hand, c-Jun N-terminal Kinase (JNK) pathway mediates the activation and transcription of c-Jun, which is required for interleukin-1 (IL-1)-induction of matrix metalloproteinases-13 (MMP-13) in OA pathogenesis. Therefore, the selective inhibition of iNOS and c-Jun is a promising target for treatment and prevention of OA. The purpose of the study was to investigate the inhibitory effects of pentosan polysulfate (PPS) on IL-1β-induced iNOS, c-Jun and HIF-α isoforms upregulation in canine articular chondrocytes (CACs). Primary (P0) chondrocytes were isolated and cultured from femoral head cartilages of three (3) dogs. First passage (P1) chondrocytes were preincubated with 0, 1, 5, 15 and 40 μg/mL of PPS for 4 hr before treatment with 10 ng/mL rhIL-1β for a further 8 hr. In addition, we evaluated the effects of single and multiple cytokine with or without LPS on iNOS protein induction. PPS significantly inhibited (P < 0.05) IL-1β-induced iNOS, c-Jun and HIF-1α mRNA upregulation in a dose-dependent pattern. iNOS mRNA was significantly inhibited at 15 and 40 μg/mL whereas c-Jun and HIF-1α were significantly downregulated at 5, 15 and 40 μg/mL of PPS compared to chondrocytes treated with only rhIL-1β. Intriguingly, CACs were recalcitrant to single IL-1β, TNF-α or LPS-induction of iNOS protein including to a combination of IL-1β+TNF-α, IL-1β+LPS except to TNF-α+LPS and IL-1β+TNF-α+LPS suggestive of a protective mechanism from iNOS detrimental effects on perpetuating OA. IL-1β+TNF-α+LPS-induced iNOS protein expression was significantly abrogated by PPS. We demonstrate for the first time that PPS is a novel inhibitor of IL-1β-induced iNOS, c-Jun, and HIF-1α mRNA upregulation and iNOS protein induction which may be beneficial for prevention and treatment OA.
| S-EPMC5417682 | biostudies-literature