Hypoxia and Wnt signaling inversely regulate expression of chondroprotective molecule ANP32A in articular cartilage

Quintiens, Jolien; A, De Roover; Cornelis, F.M.; Escribano-Núñez, Ana; Sermon, An; Pazmino, Sofia; Monteagudo, S.; Lories, Rik

doi:10.1016/j.joca.2022.10.019

Cited by 4 publications

(2 citation statements)

References 46 publications

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“…While other chondrogenic cell lines, such as C28/I2, ATDC5, and C3H10T1/2, have been used for in vitro studies, they are not suitable for genome-wide growth-plate chondrocyte screening due to limitations of culture conditions and/or recapitulation of an articular cartilage phenotype. 57 , 58 , 59 , 60 , 61 , 62 , 63 , 64 , 65 Although use of the GPLC cell line enabled genome-wide screening, our chondrocyte maturation assay favors detection of KOs that have a proliferative advantage (most abundant KOs within the top/bottom 10% of mature/immature cells were selected). To account for this potential shortcoming, we considered background depletion of maturing cells.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide CRISPR screening of chondrocyte maturation newly implicates genes in skeletal growth and height-associated GWAS loci

Baronas¹,

Bartell²,

Eliasen³

et al. 2023

Cell Genomics

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Section: Discussionmentioning

confidence: 99%

Genome-wide CRISPR screening of chondrocyte maturation newly implicates genes in skeletal growth and height-associated GWAS loci

Baronas¹,

Bartell²,

Eliasen³

et al. 2023

Cell Genomics

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“…It has been reported that Wnts are crucial for articular cartilage and bone homeostasis, as we found a decreased expression of Wnt signaling in human OA cartilage compared to controls. But some other researchers investigated that cartilage can be damaged and the stable articular chondrocyte phenotype lost as a result of excessive Wnt signaling [ 41 ]. Interestingly, in this study, we revealed that Wnt signaling could be depressed because of GEM knockdown, inducing a loss in cartilage.…”

Section: Discussionmentioning

confidence: 99%

Decreased expression of GEM in osteoarthritis cartilage regulates chondrogenic differentiation via Wnt/β-catenin signaling

Gan,

Deng,

Wei

et al. 2023

J Orthop Surg Res

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Background GEM (GTP-binding protein overexpressed in skeletal muscle) is one of the atypical small GTPase subfamily members recently identified as a regulator of cell differentiation. Abnormal chondrogenesis coupled with an imbalance in the turnover of cartilaginous matrix formation is highly relevant to the onset and progression of osteoarthritis (OA). However, how GEM regulates chondrogenic differentiation remains unexplored. Methods Cartilage tissues were obtained from OA patients and graded according to the ORASI and ICRS grading systems. The expression alteration of GEM was detected in the Grade 4 cartilage compared to Grade 0 and verified in OA mimic culture systems. Next, to investigate the specific function of GEM during these processes, we generated a Gem knockdown (Gem-Kd) system by transfecting siRNA targeting Gem into ATDC5 cells. Acan, Col2a1, Sox9, and Wnt target genes of Gem-Kd ATDC5 cells were detected during induction. The transcriptomic sequencing analysis was performed to investigate the mechanism of GEM regulation. Wnt signaling pathways were verified by real-time PCR and immunoblot analysis. Finally, a rescue model generated by treating Gem-KD ATDC5 cells with a Wnt signaling agonist was established to validate the mechanism identified by RNA sequencing analysis. Results A decreased expression of GEM in OA patients’ cartilage tissues and OA mimic chondrocytes was observed. While during chondrogenesis differentiation and cartilage matrix formation, the expression of GEM was increased. Gem silencing suppressed chondrogenic differentiation and the expressions of Acan, Col2a1, and Sox9. RNA sequencing analysis revealed that Wnt signaling was downregulated in Gem-Kd cells. Decreased expression of Wnt signaling associated genes and the total β-CATENIN in the nucleus and cytoplasm were observed. The exogenous Wnt activation exhibited reversed effect on Gem loss-of-function cells. Conclusion These findings collectively validated that GEM functions as a novel regulator mediating chondrogenic differentiation and cartilage matrix formation through Wnt/β-catenin signaling.

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IRF1-mediated upregulation of PARP12 promotes cartilage degradation by inhibiting PINK1/Parkin dependent mitophagy through ISG15 attenuating ubiquitylation and SUMOylation of MFN1/2

Deng,

Long,

et al. 2024

Bone Res

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Osteoarthritis (OA) is an age-related cartilage-degenerating joint disease. Mitochondrial dysfunction has been reported to promote the development of OA. Poly (ADP-ribose) polymerase family member 12 (PARP12) is a key regulator of mitochondrial function, protein translation, and inflammation. However, the role of PARP12 in OA-based cartilage degradation and the underlying mechanisms are relatively unknown. Here, we first demonstrated that PARP12 inhibits mitophagy and promotes OA progression in human OA cartilage and a monosodium iodoacetate-induced rat OA model. Using mass spectrometry and co-immunoprecipitation assay, PARP12 was shown to interact with ISG15, upregulate mitofusin 1 and 2 (MFN1/2) ISGylation, which downregulated MFN1/2 ubiquitination and SUMOylation, thereby inhibiting PINK1/Parkin-dependent chondrocyte mitophagy and promoting cartilage degradation. Moreover, inflammatory cytokine-induced interferon regulatory factor 1 (IRF1) activation was required for the upregulation of PARP12 expression, and it directly bound to the PARP12 promoter to activate transcription. XAV-939 inhibited PARP12 expression and suppressed OA pathogenesis in vitro and in vivo. Clinically, PARP12 can be used to predict the severity of OA; thus, it represents a new target for the study of mitophagy and OA progression. In brief, the IRF1-mediated upregulation of PARP12 promoted cartilage degradation by inhibiting PINK1/Parkin-dependent mitophagy via ISG15-based attenuation of MFN1/2 ubiquitylation and SUMOylation. Our data provide new insights into the molecular mechanisms underlying PARP12-based regulation of mitophagy and can facilitate the development of therapeutic strategies for the treatment of OA.

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Hypoxia and Wnt signaling inversely regulate expression of chondroprotective molecule ANP32A in articular cartilage

Cited by 4 publications

References 46 publications

Genome-wide CRISPR screening of chondrocyte maturation newly implicates genes in skeletal growth and height-associated GWAS loci

Genome-wide CRISPR screening of chondrocyte maturation newly implicates genes in skeletal growth and height-associated GWAS loci

Decreased expression of GEM in osteoarthritis cartilage regulates chondrogenic differentiation via Wnt/β-catenin signaling

IRF1-mediated upregulation of PARP12 promotes cartilage degradation by inhibiting PINK1/Parkin dependent mitophagy through ISG15 attenuating ubiquitylation and SUMOylation of MFN1/2

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