The Hippo-YAP Signaling Pathway in Osteoarthritis and Rheumatoid Arthritis

Disrupted intestinal epithelial barrier function has been proposed to be integral to rheumatoid arthritis (RA) progression and pathogenesis. To further define the molecular pathways in synovial inflammation and a response of the intestinal tissues, we have now used a rat model of mono-joint inflammatory arthritis, induced by intra-articular injection (IAI) of Complete Freunds adjuvant (CFA). The predominant inflammatory response of a single injection of the adjuvant into the knee joint resulted in rapid and reproducible formation of a fibrotic myeloid-infiltrated synovial pannus. Our aim was to determine how intestinal tissues, including the proximal and distal ileum and distal colon, respond to inflammatory changes in the synovium in a temporally coordinated manner by comparing their transcriptomic landscapes using RNASeq analyses. We confirmed the timeline of joint inflammation by knee joint swelling measurement, synovial fluid levels of the acute phase protein Inter-α-trypsin inhibitor heavy chains (ITIH) and demonstrated a self-correcting response of trabecular and cortical bone to the CFA challenge. Intestine-specific responses were monitored by 16S microbiome amplicon sequencing, histopathology for mucus layer integrity, and immune cell immunohistochemistry. We present data showing that the intestinal tissue response to the acute joint inflammation was region specific, with the ileum primarily responding with increased mucus secretion and silencing of T cell specific pathways, whereas the colon showed a transient upregulation of macrophages, with a broader suppression of immune related and metabolic pathway related transcripts. However, at no time after CFA-IAI were there significant changes in the fecal microbiome composition of the ileum or the colon. In summary, our data report for the first time a suppression of intestinal inflammatory and immune responses following the induction of joint inflammation and only minimal and transient changes in the microbiome.

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ER stress-induced YAP upregulation leads to chondrocyte phenotype loss in age-related osteoarthritis

Gao,

Wei,

Peng

et al. 2024

Front. Pharmacol.

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BackgroundOsteoarthritis (OA) is a common degenerative joint disease, leading to pain and restricted mobility. Age-related endoplasmic reticulum (ER) stress has been implicated in the pathogenesis of OA, but the underlying mechanisms remain unclear. This study aims to explore the relationship between age-related ER stress, YAP overexpression, and chondrocyte phenotype loss in the development of OA.MethodsCartilage samples were collected from patients undergoing amputation, and age-related ER stress markers and YAP expression were assessed using immunohistochemical staining and qPCR. Transgenic mice with cartilage-specific YAP overexpression (YAPOE) were created, and Pamrevlumab was administered to evaluate its therapeutic effects.ResultsHigher expression of ER stress markers and YAP were showed in aged tissues compared to younger tissues. YAP overexpression led to decreased levels of cartilage phenotype markers and increased osteogenesis-related proteins. In vivo, YAPOE mice exhibited OA-like cartilage degeneration, which was mitigated by Pamrevlumab treatment.ConclusionAge-related ER stress induces YAP overexpression, contributing to OA pathogenesis. Pamrevlumab effectively prevents this phenotype loss in YAPOE mice, suggesting its potential as a therapeutic agent for OA. These findings provide new insights into the molecular mechanisms of OA and highlight the importance of targeting the ER stress-YAP-CTGF signaling pathway in OA treatment and prevention.

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The Hippo-YAP Signaling Pathway in Osteoarthritis and Rheumatoid Arthritis

Cited by 4 publications

References 124 publications

Application of kartogenin for the treatment of cartilage defects: current practice and future directions

Application of kartogenin for the treatment of cartilage defects: current practice and future directions

Evidence of Silencing of Intestinal Inflammatory and Immune Transcripts Following Induction of Joint Inflammation

ER stress-induced YAP upregulation leads to chondrocyte phenotype loss in age-related osteoarthritis

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