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1.
Osteoarthritis Cartilage ; 32(3): 266-280, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38035977

RESUMO

OBJECTIVE: Osteoarthritis (OA) is often accompanied by debilitating pain that is refractory to available analgesics due in part to the complexity of signaling molecules that drive OA pain and our inability to target these in parallel. Fatty acid binding protein 5 (FABP5) is a lipid chaperone that regulates inflammatory pain; however, its contribution to OA pain has not been characterized. DESIGN: This combined clinical and pre-clinical study utilized synovial tissues obtained from subjects with end-stage OA and rats with monoiodoacetate-induced OA. Cytokine and chemokine release from human synovia incubated with a selective FABP5 inhibitor was profiled with cytokine arrays and ELISA. Immunohistochemical analyses were conducted for FABP5 in human and rat synovium. The efficacy of FABP5 inhibitors on pain was assessed in OA rats using incapacitance as an outcome. RNA-seq was then performed to characterize the transcriptomic landscape of synovial gene expression in OA rats treated with FABP5 inhibitor or vehicle. RESULTS: FABP5 was expressed in human synovium and FABP5 inhibition reduced the secretion of pronociceptive cytokines (interleukin-6 [IL6], IL8) and chemokines (CCL2, CXCL1). In rats, FABP5 was upregulated in the OA synovium and its inhibition alleviated incapacitance. The transcriptome of the rat OA synovium exhibited >6000 differentially expressed genes, including the upregulation of numerous pronociceptive cytokines and chemokines. FABP5 inhibition blunted the upregulation of the majority of these pronociceptive mediators. CONCLUSIONS: FABP5 is expressed in the OA synovium and its inhibition suppresses pronociceptive signaling and pain, indicating that FABP5 inhibitors may constitute a novel class of analgesics to treat OA.


Assuntos
Citocinas , Osteoartrite , Humanos , Ratos , Animais , Citocinas/metabolismo , Osteoartrite/metabolismo , Dor/metabolismo , Quimiocinas/metabolismo , Membrana Sinovial/metabolismo , Analgésicos , Proteínas de Ligação a Ácido Graxo/genética
2.
Artigo em Inglês | MEDLINE | ID: mdl-37358789

RESUMO

Background: Osteoarthritis (OA) is a progressive degenerative joint disease that presents with significant pain and functional disability. The endocannabinoid 2-arachidonoylglycerol activates cannabinoid receptors to reduce pain while its hydrolysis by the enzyme monoacylglycerol lipase (MAGL) generates arachidonic acid, the direct precursor to proalgesic eicosanoids synthesized by cyclooxygenase-2 (COX-2), highlighting the potential for crosstalk between MAGL and COX-2. While COX-2 expression in human OA cartilage has been described, the distribution of MAGL in knee osteochondral tissue has not been reported and was the goal of the current study. Methods: MAGL and COX-2 expression in International Cartilage Repair Society grade II and grade IV knee osteochondral tissue obtained from male and female subjects with OA was investigated through immunohistochemistry. Immunolocalization of both proteins was investigated within articular cartilage and subchondral bone. Results: MAGL is expressed throughout the cartilage of grade II arthritic tissue, with prominent distribution in the superficial and deep zones. Elevated expression of MAGL was evident in grade IV samples, with additional distribution observed in subchondral bone. COX-2 expression followed a similar pattern, with uniform distribution in cartilage and increased expression in grade IV tissue. Conclusions: This study establishes MAGL expression in arthritic cartilage and subchondral bone of subjects with OA. The proximity between MAGL and COX-2 suggests the potential for crosstalk between endocannabinoid hydrolysis and eicosanoid signaling in the maintenance of OA pain.

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