Hypoxia/reoxygenation activates the JNK pathway and accelerates synovial senescence

Abstract

Hypoxia/reoxygenation (H/r) may play an important role via senescence in the mechanism of osteoarthritis (oa) development. The synovial membrane is highly sensitive to H/r due to its oxygen consumption feature. excessive mechanical loads and oxidative stress caused by H/r induce a senescence-associated secretory phenotype (SaSP), which is related to the development of oa. The aim of the present study was to investigate the differences of SaSP manifestation in synovial tissue masses between tissues from healthy controls and patients with oa. The present study used tumor necrosis factor-α (TnF-α) to pre-treat synovial tissue and fibroblast-like synoviocytes (FLS) to observe the effect of inflammatory cytokines on the synovial membrane before H/R. It was determined that H/R increased interleukin (IL)-1β and il-6 expression levels in TnF-α-induced cell culture supernatants, increased the proportion of Sa-β-gal staining, and increased the expression levels of high mobility group box 1, caspase-8, p16, p21, matrix metalloproteinase (MMP)-3 and MMP-13 in the synovium. Furthermore, H/R opened the mitochondrial permeability transition pore, caused the loss of mitochondrial membrane potential (ΔΨm) and increased the release of reactive oxygen species (roS). Moreover, H/r caused the expansion of the mitochondrial matrix and rupture of the mitochondrial extracorporeal membrane, with a decrease in the number of cristae. in addition, H/r induced activation of the JnK signaling pathway in FlS to induce cell senescence. Thus, the present results indicated that H/r may cause inflammation and escalate synovial inflammation induced by TnF-α, which may lead to the pathogenesis of oa by increasing changes in synovial SaSP and activating the JnK signaling pathway. Therefore, further studies expanding on the understanding of the pathogenesis of H/r etiology in oa are required.

The inflammatory speech of fibroblasts

“…15‐hydroxyprostaglandin dehydrogenase is reduced in OA compared to normal synovium as well as in cultured OA‐FLS compared to normal FLS, 223 suggesting a propensity of OA‐FLS to promote and prolong inflammation. Antioxidant activity of OA‐FLS is also decreased by IL‐1β, with increased nitric oxide and reactive oxygen species detected in response to IL‐1β and TNF‐α 214,226,229 . Finally, cartilage wear particles act similar to TNF‐α and IL‐1β in OA‐FLS in vitro to promote inflammatory mediators including nitric oxide, PGE2, IL‐6, and IL‐8 214 …”

“…For instance, cultured FLS produce IL-1β and IL-6 in response to TNFα. 229 In contrast, expression of inflammatory inhibitors can also be reduced in OA-FLS, such as 15-hydroxyprostaglandin dehydrogenase, which is responsible for the inactivation of PGE2, an inflammatory mediator released by OA-FLS via IL-1β -induced cyclooxygenase-2 activity. 214,246 15-hydroxyprostaglandin dehydrogenase is reduced in OA compared to normal synovium as well as in cultured OA-FLS compared to normal FLS, 223 suggesting a propensity of OA-FLS to promote and prolong inflammation.…”

“…Of particular interest for this review is the ability of OA‐FLS to produce inflammatory cytokines in response to factors in the environment. For instance, cultured FLS produce IL‐1β and IL‐6 in response to TNF‐α 229 . In contrast, expression of inflammatory inhibitors can also be reduced in OA‐FLS, such as 15‐hydroxyprostaglandin dehydrogenase, which is responsible for the inactivation of PGE2, an inflammatory mediator released by OA‐FLS via IL‐1β ‐induced cyclooxygenase‐2 activity 214,246 .…”

Synovial Fibrosis Involvement in Osteoarthritis

“…Hypoxia refers to a decrease in oxygen tension in tissues, and the central effector of the hypoxia response is the transcription factor hypoxia-inducible factor (HIF). In the hypoxic state, the alpha subunit in HIF is no longer hydroxylated but accumulates and translocates to the nucleus, where it binds to the beta subunit of HIF and exerts its function as a transcription factor ( 54 ). The genes encoding VEGF, TGF-β, and IGF-2, which are regulated by HIF-1α, and angiotensin II, which is modulated by HIF-2α, are all important profibrotic factors ( 45 ).…”

The Contributive Role of IGFBP-3 and Mitochondria in Synoviocyte-Induced Osteoarthritis through Hypoxia/Reoxygenation Injury: A Pathogenesis-Focused Literature Review

“…Traditionally considered not associated with transient episodes of ischemia and/or hypoxia, osteoarthritis is nowadays receiving great attention as a clinical manifestation of I-R and/or H/R injury [17,54,65]. Hypoxia is recognized as an important feature of the joint microenvironment, especially in the perpetuation of joint destruction in OA [54].…”