No abstract

Chronic, low-grade inflammation in osteoarthritis (OA) contributes to symptoms and disease progression. Effective disease-modifying medical OA therapies are lacking, but better understanding inflammatory pathophysiology in OA could lead to transformative therapy. Networks of diverse innate inflammatory danger signals, including complement and alarmins, are activated in OA. Through inflammatory mediators, biomechanical cartilage injury and oxidative stress compromise chondrocyte viability and reprogram viable chondrocytes to hypertrophic differentiation and proinflammatory, and procatabolic responses in mechanistically similar ways. Integral to this reprogramming are certain ‘switching’ pathways in transcriptional signals, other than the well-characterized effects of NFκB and mitogen-activated protein kinase signalling. HIF-2α transcriptional signalling and ZIP8-mediated Zn2+ uptake, with downstream MTF1 transcriptional signalling, have been implicated in chondrocyte reprogramming, but further validation is required. Permissive factors in procatabolic reprogramming of OA chondrocytes by inflammatory mediators also have come to light, including impaired bioenergetics, such as altered mitochondrial function and decreased activity of the bioenergy sensors AMPK and SIRT1. These factors interact with molecular inflammatory responses and proteostasis mechanisms that normally resolve cell stress, such as the unfolded protein response and autophagy. Bioenergy-sensing by AMPK and SIRT1 modulates proteostasis and provides ‘stop signals’ for oxidative stress, inflammatory, and matrix catabolic processes in chondrocytes. The complexity of molecular inflammatory processes in OA, and the involvement of multiple inflammatory mediators in tissue repair responses, raises daunting questions about how to therapeutically target inflammatory processes and macroscopic inflammation in OA. Bioenergy sensing might provide a pragmatic ‘entry point’ for novel strategies to limit OA progression.

Objective. In gout, incompletely defined molecular factors alter recognition of dormant articular and bursal monosodium urate monohydrate (MSU) crystal deposits, thereby inducing self-limiting bouts of characteristically severe neutrophilic inflammation. To define primary determinants of cellular recognition, uptake, and inflammatory responses to MSU crystals, we conducted a study to test the role of Toll-like receptor 2 (TLR-2), TLR-4, and the cytosolic TLR adapter protein myeloid differentiation factor 88 (MyD88), which are centrally involved in innate immune recognition of microbial pathogens.Methods. We isolated bone marrow-derived macrophages (BMDMs) in TLR-2 ؊/؊ , TLR-4 ؊/؊ , MyD88 ؊/؊ , and congenic wild-type mice, and assessed phagocytosis and cytokine expression in response to endotoxin-free MSU crystals under serum-free conditions. MSU crystals also were injected into mouse synovium-like subcutaneous air pouches.Results. TLR-2 ؊/؊ , TLR-4 ؊/؊ , and MyD88 ؊/؊ BMDMs demonstrated impaired uptake of MSU crystals in vitro. MSU crystal-induced production of interleukin-1␤ (IL-1␤), tumor necrosis factor ␣, keratinocyte-derived cytokine/growth-related oncogene ␣, and transforming growth factor ␤1 also were significantly suppressed in TLR-2 ؊/؊ and TLR-4 ؊/؊ BMDMs and were blunted in MyD88 ؊/؊ BMDMs in vitro. Neutrophil influx and local induction of IL-1␤ in subcutaneous air pouches were suppressed 6 hours after injection of MSU crystals in TLR-2 ؊/؊ and TLR-4 ؊/؊ mice and were attenuated in MyD88 ؊/؊ mice.Conclusion. The murine host requires TLR-2, TLR-4, and MyD88 for macrophage activation and development of full-blown neutrophilic, air pouch inflammation in response to MSU crystals. Our findings implicate innate immune cellular recognition of naked MSU crystals by specific TLRs as a major factor in determining the inflammatory potential of MSU crystal deposits and the course of gouty arthritis.

Objective. Interleukin-1␤ (IL-1␤) is a key cytokine linked to the pathogenesis of acute arthritis. Caspase 1, neutrophil elastase, and chymase all process proIL-1␤ to its biologically active form. This study was undertaken to examine the potential contributions of each of these proteases in experimental models of inflammatory arthritis.Methods. Conclusion. The production of IL-1␤ by neutrophils and mast cells is not exclusively dependent on caspase 1, and other proteases can compensate for the loss of caspase 1 in vivo. These pathways might therefore compromise the caspase 1-targeted therapies in neutrophil-predominant arthritis.