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Review
. 2022 May;18(5):258-275.
doi: 10.1038/s41584-022-00749-9. Epub 2022 Feb 14.

Synovial inflammation in osteoarthritis progression

Elsa Sanchez-Lopez #  1 , Roxana Coras #  2   3 , Alyssa Torres  2 , Nancy E Lane  4 , Monica Guma  5   6   7
Affiliations
Review

Synovial inflammation in osteoarthritis progression

Elsa Sanchez-Lopez et al. Nat Rev Rheumatol. 2022 May.

Abstract

Osteoarthritis (OA) is a progressive degenerative disease resulting in joint deterioration. Synovial inflammation is present in the OA joint and has been associated with radiographic and pain progression. Several OA risk factors, including ageing, obesity, trauma and mechanical loading, play a role in OA pathogenesis, likely by modifying synovial biology. In addition, other factors, such as mitochondrial dysfunction, damage-associated molecular patterns, cytokines, metabolites and crystals in the synovium, activate synovial cells and mediate synovial inflammation. An understanding of the activated pathways that are involved in OA-related synovial inflammation could form the basis for the stratification of patients and the development of novel therapeutics. This Review focuses on the biology of the OA synovium, how the cells residing in or recruited to the synovium interact with each other, how they become activated, how they contribute to OA progression and their interplay with other joint structures.

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Figures

Fig. 1 ∣
Fig. 1 ∣. Synovial inflammation and fibrosis in osteoarthritis.
Haematoxylin and eosin staining of synovial tissue from patients who underwent total knee replacement. a,b ∣ Features of an inflammatory phenotype are highlighted in the magnified insets, including hyperplasia of the synovial lining (asterisk in part a), and cellular infiltrates and vascularization in the sublining layer (asterisk in part b). c,d ∣ Features of a fibrotic phenotype are highlighted in the magnified insets, including fibrosis in the sublining layer (asterisks in parts c and d).
Fig. 2 ∣
Fig. 2 ∣. Osteoarthritis risk factors and synovitis.
Among the risk factors associated with osteoarthritis (OA) development and progression, trauma, mechanical loading, comorbidities and diet–microbiome interactions are also related to synovitis. Injury to the meniscus or ligaments and intra-articular fractures lead to the development of synovitis. Aberrant and excessive loading is a known risk factor for developing OA, and subseguent shear stress and compression induce production of inflammatory mediators such as nitric oxide synthase (NOS), IL-6 and IL-8, which contribute to OA pathogenesis. Synovitis has also been related to obesity and type 2 diabetes mellitus. Dietary habit, which has been demonstrated to increase pain prevalence in patients with OA, is one of the factors that influence the composition of the gut microbiome. Microbial dysbiosis (that is, alteration in gut microbiome composition) favours inflammation and metabolic syndrome, as well as changes in intestinal permeability and metabolic endotoxaemia, which correlates with recruitment of activated pro-inflammatory synovial macrophages. LPS, lipopolysaccharide.
Fig. 3 ∣
Fig. 3 ∣. Molecular mediators that contribute to synovial inflammation in osteoarthritis.
Ageing and mitochondrial damage increase reactive oxygen species (ROS) production and mitochondrial DNA mutations and can prolong the production of pro-inflammatory cytokines such as IL-1β and IL-6. Senescent cells are associated with age-related pathological conditions such as osteoarthritis (OA), and several senescence-associated secretory phenotype (SASP) factors are inflammatory mediators. Cellular metabolites, such as nitric oxide (NO), succinate and prostaglandins, as well as other bioactive lipids, contribute to inflammation and cartilage damage. NO levels are elevated in chondrocytes and pro-inflammatory macrophages in patients with OA. Succinate accumulates in inflammatory macrophages and supports their pro-inflammatory phenotype. The succinate receptor SUCNR1 is activated by soluble succinate and boosts IL-4 production. Prostaglandin E2 (PGE2) is considered the major contributor to inflammatory pain in the joint and signals through receptors such as EP4, thereby enhancing production of the pro-inflammatory factors NO (by increasing expression of inducible nitric oxide synthase (iNOS)) and IL-6, which also contributes to synovitis and increases hyperalgesia. PGD2 is also enriched in synovial fluid from patients with OA. Damage-associated molecular patterns (DAMPs) and alarmins, in the context of mechanical stress, interact with Toll-like receptors (TLRs), receptor for advanced glycation end products (RAGE) and other pattern recognition receptors to initiate and propagate inflammation. DAMPs such as high mobility group protein B1 (HMGB1) and heat shock proteins (HSPs) are abundant in OA synovial fluid. S100 family proteins are also upregulated in inflamed synovial tissue. Ectopic deposition of hydroxyapatite crystals, calcium pyrophosphate dihydrate (CPPD) microcrystals and monosodium urate (MSU) crystals, which may signal through P2X7 (depicted) or CD11b,CD16 and CD14 (not shown), as well as ATP released from dying cells, are detected by macrophages and trigger NLRP3 inflammasome activation and IL-1β and IL-18 production. MSU crystals correlate with levels of IL-1β and IL-18 in synovial fluid. Complement factors are highly expressed in OA and play a role in OA pathogenesis. Diet is one of the determining factors of microbiome composition. An altered gut microbial composition is associated with increased intestinal permeability and metabolic endotoxaemia (systemic lipopolysaccharide (LPS)), which is associated with recruitment of pro-inflammatory macrophages in the synovium.
Fig. 4 ∣
Fig. 4 ∣. Cellular crosstalk in synovitis and OA progression.
Activated fibroblast-Like synoviocytes (FLS) in the osteoarthritis (OA) synovium secrete, among other factors, cytokines, growth factors, matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs), which contribute to macrophage activation and stimulate catabolic pathways in chondrocytes. Similarly, activated macrophages secrete pro-inflammatory mediators that stimulate FLS and chondrocytes, promoting the degradation of extracellular matrix (ECM) components. ECM degradation products further activate both FLS and macrophages, resulting in a repeating cycle of inflammation and cartilagedegradation. CCL2, CC-chemokine ligand 2; MCP1, monocyte chemoattractant protein 1; sICAM1, soluble intercellular adhesion molecule 1; sVCAM1, soluble vascular cell adhesion molecule 1; TGFβ, transforming growth factor-β; TNF, tumour necrosis factor; VEGF, vascular endothelial growth factor.
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