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• W3020051030 abstract "Purpose: Osteoarthritis (OA), the most common joint disease for which no effective therapy currently exists, has a complex pathogeny with diverse interacting factors causing articular cartilage damage and alterations in other joint tissues. We previously described an association between polymorphisms in the acidic leucine-rich nuclear phosphoprotein-32A (ANP32A) gene and OA. Recently, we discovered that ANP32A protects against OA by promoting expression of antioxidant enzyme ATM in cartilage, thereby reducing oxidative stress. However, incomplete rescue of OA features upon antioxidant treatment suggests the existence of additional ANP32A-dependent regulatory mechanisms. Here, we uncover a novel regulatory role of ANP32A in cartilage. Methods: We analyzed our earlier reported genome-wide transcriptome data from articular cartilage of Anp32a-/- mice using a novel approach, namely Upstream Regulator Analysis from Ingenuity Pathway Analysis (IPA) software. The murine chondrogenic progenitor ATDC5 cell line was used to generate a stable Anp32a knockdown (KD) cell line, and micromass cultures were performed to induce a chondrogenic differentiation program. We performed real-time qPCR analyses to determine the expression of genes involved in chondrogenesis and Wnt signaling. Alcian blue and Safranin O staining were performed to determine proteoglycan content of the micromasses. Picrosirius red and Alizarin red staining were performed to evaluate collagen fibers and calcium deposition, respectively. Primary human articular chondrocytes were isolated from hips of patients undergoing hip replacement surgery. Immunohistochemistry was used to detect protein expression of Wnt target gene TCF1 in Anp32a-/- and wild-type mice. We determined the expression of ANP32A and Wnt target genes in articular cartilage of OA patients (n=21) by RNA sequencing. Co-immunoprecipitation (co-IP) analysis was performed to explore protein-protein interactions between ANP32A and Wnt signaling components. Chromatin-immunoprecipitation qPCR (ChIP-qPCR) analysis was performed to investigate binding of ANP32A to Wnt target genes and changes in histone acetylation markers. Immunofluorescence (IF) was used to determine the subcellular localization of ANP32A upon Wnt activation. Results: Upstream Regulator Analysis of differentially expressed genes in Anp32a-/- mouse cartilage suggested that ANP32A may regulate the Wnt signaling pathway, a cascade that when hyper-activated leads to joint disease and that is increasingly recognized as a target for therapy in OA. In the ATDC5 chondrogenic model, in which Wnt signaling is known to block the differentiation program, Anp32a KD strongly reduced chondrogenic differentiation. Effectively, Anp32a KD enhanced Wnt signaling activation in this cartilage differentiation model. Similarly, Wnt signaling was hyper-activated in the articular cartilage of Anp32a-/- mice and in Anp32a-silenced primary human articular chondrocytes. Expression of ANP32A and Wnt direct target genes negatively correlated in human OA cartilage, indicating that the link ANP32A/Wnt is clinically relevant in OA pathogenesis. Mechanistic insights using CoIP, ChIP-qPCR and IF analyses revealed that ANP32A directly regulates specific Wnt target genes, via histone acetylation masking. Conclusions: Our studies demonstrate that ANP32A is a converging node regulating a complex protective network against OA. ANP32A deficiency results in Wnt signaling hyper-activation, occurring concomitantly with excessive oxidative stress. These insights have relevant clinical implications in OA, as co-treatment with Wnt inhibitors and antioxidants might have synergistic therapeutic effects on disease progression." @default.
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• W3020051030 date "2020-04-01" @default.
• W3020051030 modified "2023-09-26" @default.
• W3020051030 title "ANP32A is a hub molecule regulating a protective network against osteoarthritis" @default.
• W3020051030 doi "https://doi.org/10.1016/j.joca.2020.02.137" @default.
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