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--- spinal_osteoarthritis [2024/11/05 19:42] – created - external edit 127.0.0.1
+++ spinal_osteoarthritis [2025/07/09 14:58] (current) – [Pathogenesis] administrador
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 ===== Pathogenesis =====
+[[Osteoarthritis Pathogenesis]].
-Osteoarthritis (OA) is a degenerative joint disease characterized by the breakdown of cartilage in joints, leading to pain, stiffness, and loss of function. The pathogenesis of osteoarthritis involves complex interactions between mechanical factors, biochemical processes, and genetic predispositions. Here's a brief overview of the key factors involved:
-Cartilage Degradation: The primary feature of OA is the breakdown of cartilage, the smooth tissue that covers the ends of bones in a joint. This degradation occurs due to an imbalance between cartilage synthesis and degradation. Factors such as mechanical stress, inflammation, and oxidative stress contribute to the degradation of cartilage matrix components like collagen and proteoglycans.
-Mechanical Stress: Excessive mechanical stress on joints, either from obesity, repetitive use, or joint misalignment, is a significant risk factor for OA. Mechanical stress can lead to cartilage damage directly through wear and tear and indirectly by triggering inflammatory and catabolic pathways.
-Inflammation: Low-grade inflammation within the joint is a key component of OA pathogenesis. Inflammatory mediators such as cytokines (e.g., interleukin-1β, tumor necrosis factor-alpha) and enzymes (e.g., matrix metalloproteinases) contribute to cartilage breakdown and synovial inflammation.
-Synovial Changes: The synovium, the membrane lining the joint capsule, undergoes changes in OA. Synovial inflammation and thickening occur, leading to increased production of inflammatory cytokines and enzymes that contribute to cartilage degradation.
-Genetic Factors: Genetic predisposition plays a role in OA development. Certain gene variants associated with cartilage structure, inflammation, and joint function can increase the risk of developing OA. However, genetic factors alone are not sufficient to cause OA, and environmental factors also play a significant role.
-Metabolic Factors: Metabolic factors such as obesity, insulin resistance, and dyslipidemia are associated with an increased risk of OA, particularly in weight-bearing joints like the knees and hips. These factors contribute to systemic inflammation and altered joint mechanics.
-Overall, osteoarthritis is a multifactorial disease with contributions from mechanical, biochemical, genetic, and environmental factors. Understanding the underlying mechanisms involved in OA pathogenesis is essential for developing effective strategies for prevention and treatment.
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-[[Transferrin receptor]]-1 (TfR1) plays important roles in controlling cellular [[iron]] levels, but its role in [[osteoarthritis]] pathology is unknown.
-Wang et al. aim to investigate the role of TfR1 in OA progression and its underlying mechanisms.
-TfR1 expression in cartilage during OA development were examined both in vivo and in vitro. Then [[IL-1β]] was used to induce [[chondrocyte]]s [[degeneration]] in vitro and TfR1 siRNA was used for observing the effect of TfR1 in modulating iron [[homeostasis]], mitochondrial function and degrading [[enzyme]]s expression. Also the inhibitor of TfR1 was exploited to analyze the protective effect of TfR1 inhibition in vivo.
-TfR1 is elevated in OA cartilage and contributes to OA [[inflammation]] condition. Excess iron not only results in [[oxidative stress damage]] and sensitizes chondrocytes to [[ferroptosis]], but also triggers c-GAS/STING-mediated inflammation by promoting mitochondrial destruction and the release of mtDNA. Silencing TfR1 using TfR1 siRNA not only reduced iron content in chondrocytes and inhibited oxidative stress, but also facilitated the mitophagy process and suppressed mtDNA/cGAS/STING-mediated inflammation. Importantly, we also found that Ferstatin II, a novel and selective TfR1 inhibitor, could substantially suppress TfR1 activity both in vivo and in vitro and ameliorated cartilage degeneration.
-The work demonstrates that TfR1 mediated iron influx plays important roles in chondrocytes degeneration and OA pathogenesis, suggesting that maintaining iron homeostasis through the targeting of TfR1 may represent a novel therapeutic strategy for the treatment of OA
-((Wang W, Ma Z, Feng X, Ren J, Sun S, Shao Y, Zhang W, Yang X, Zhang J, Jing X. TfR1 mediated iron metabolism dysfunction as a potential therapeutic target for osteoarthritis. Arthritis Res Ther. 2024 Mar 16;26(1):71. doi: 10.1186/s13075-024-03304-x. PMID: 38493104.))
 ===== Osteoarthritis pain =====