Osteoarthritis (OA) is a well-known disease that is part of the aging process and also one of the most common diseases among mammals. Although this musculoskeletal disorder has been described in mammals of many ages, having been reported in Egyptian mummies and in dinosaurs, its exact etiology is far from being fully understood. With the graying of the world population, it is of the utmost importance to find out more about the pathogenesis of the disease and thus allow the discovery of new treatments to stop or prevent its progression. A number of risk factors have lately been identified (1). Mechanical factors, among others, are likely to play a very important role in the initiation of the disease process. Endogenous factors such as type II collagen mutation or dysplastic conditions are also known to be involved in initiating the OA process (2). There is now strong evidence that the structural changes globally observed in OA are due to a combination of factors, ranging from the mechanical to the biochemical (3,4). The disease process affects not only the cartilage, but also the entire joint structure, including the synovial membrane, subchondral bone, ligaments, and periarticular muscles. In OA synovium, the inflammatory changes that take place include synovial hypertrophy and hyperplasia with an increased number of lining cells, and also an infiltration of the sublining tissue with a mixed population of inflammatory cells. In patients with severe disease, the extent of inflammation can sometimes reach that observed in rheumatoid arthritis (RA) patients at the clinical stage (5,6). Some degree of synovitis has also been reported in even the early stages of the disease (7). Synovial inflammation is clearly reflected in many of the signs and symptoms of OA, including joint swelling and effusion, stiffness, and sometimes redness, particularly at the level of the proximal interphalangeal (PIP) and distal interphalangeal (DIP) joints.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/1529-0131%28200106%2944%3A6%3C1237%3A%3AAID-ART214%3E3.0.CO%3B2-F

Osteoarthritis, an inflammatory disease: Potential implication for the selection of new therapeutic targets

The role of synovitis in osteoarthritis pathogenesis

Accumulation and turnover of extracellular matrix components are the hallmarks of tissue injury. Fragmented hyaluronan stimulates the expression of inflammatory genes by a variety of immune cells at the injury site. Hyaluronan binds to a number of cell surface proteins on various cell types. Hyaluronan fragments signal through both Toll-like receptor (TLR) 4 and TLR2 as well as CD44 to stimulate inflammatory genes in inflammatory cells. Hyaluronan is also present on the cell surface of epithelial cells and provides protection against tissue damage from the environment by interacting with TLR2 and TLR4. Hyaluronan and hyaluronan-binding proteins regulate inflammation, tissue injury, and repair through regulating inflammatory cell recruitment, release of inflammatory cytokines, and cell migration. This review focuses on the role of hyaluronan as an immune regulator in human diseases.

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Hyaluronan as an Immune Regulator in Human Diseases

Objective

The adduction moment at the knee during gait is the primary determinant of medial-tolateral load distribution. If the adduction moment contributes to progression of osteoarthritis (OA), then patients with advanced medial tibiofemoral OA should have higher adduction moments. The present study was undertaken to investigate the hypothesis that the adduction moment normalized for weight and height is associated with medial tibiofemoral OA disease severity after controlling for age, sex, and pain level, and to examine the correlation of serum hyaluronan (HA) level with disease severity and with the adduction moment in a subset of patients.



Methods

Fifty-four patients with medial tibiofemoral OA underwent gait analysis and radiographic evaluation. Disease severity was assessed using the Kellgren-Lawrence (K-L) grade and medial joint space width. In a subset of 23 patients with available sera, HA was quantified by sandwich enzyme-linked immunosorbent assay. Pearson correlations, a random effects model, and multivariate regression models were used.



Results

The adduction moment correlated with the K-L grade in the left and right knees (r = 0.68 and r = 0.60, respectively), and with joint space width in the left and right knees (r = -0.45 and r = -0.47, respectively). The relationship persisted after controlling for age, sex, and severity of pain. The partial correlation between K-L grade and adduction moment was 0.71 in the left knees and 0.61 in the right knees. For every 1.0-unit increase in adduction moment, there was a 0.63-mm decrease in joint space width. In the subset of patients in whom serum HA levels were measured, HA levels correlated with medial joint space width (r = -0.55), but not with the adduction moment.



Conclusion

There is a significant relationship between the adduction moment and OA disease severity. Serum HA levels correlate with joint space width but not with the adduction moment. Longitudinal studies will be necessary to determine the contribution of the adduction moment, and its contribution in conjunction with metabolic markers, to progression of medial tibiofemoral OA.

https://onlinelibrary.wiley.com/doi/pdf/10.1002/1529-0131%28199807%2941%3A7%3C1233%3A%3AAID-ART14%3E3.0.CO%3B2-L

Knee adduction moment, serum hyaluronan level, and disease severity in medial tibiofemoral osteoarthritis

1. YKL-40 In a search of new bone proteins, the glycoprotein YKL-40 was identified in 1989 to be secreted in vitro in large amount by the human osteosarcoma cell line MG63. The protein was named YKL-40 based on its three N-terminal aminoacids Tyrosine (Y), Lysine (K) and Leucine (L) and its molecular mass of 40 kDa (Johansen et al. 1992). This protein was later found to be similar to a protein secreted by differentiated smooth muscle cells from swine explants of the thoracic aorta (Millis et al. 1985), to a protein isolated from the whey protein secretions of bovine mammary secretions during the nonlactating period (Rejman et al. 1988), and to a heparin binding protein secreted by human synovial cells (Nyirkos et al. 1990). In the last few years there has been a growing number of publications concerning YKL-40 and the “Story about YKL-40” has probably just started. The protein has several names: “YKL-40” (Johansen et al. 1992), “Human Cartilage glycoprotein-39 (HC gp39)” (Hakala et al. 1993), “Breast regressing protein 39 Kd (brp-39)” (Morrison et al. 1994), “38-kDa heparin-binding glycoprotein (gp38k)” (Shackelton et al. 1995), “Chitinase-3-like-1 (CHI3L1)” (Rehli et al. 1997), “Chondrex” (Harvey et al. 1998), and “40 kDa mammary gland protein (MGP-40)” (Mohanty et al. 2003). Hopefully, there will in the future be consensus of its name. In this thesis the protein is named YKL-40.

Studies on serum YKL-40 as a biomarker in diseases with inflammation, tissue remodelling, fibroses and cancer

Plasma levels of hyaluronate (HA) in patients with rheumatoid arthritis (RA) and patients with osteoarthritis (OA), measured by enzyme-linked immunosorbent assay, were compared with levels in a healthy, age-matched non-arthritic control group, in a retrospective study. Compared with the controls, the mean level of plasma HA was sevenfold higher in the RA group and twofold higher in the OA group. There was no statistically significant correlation between HA levels and 7 other clinical and biochemical parameters in patients with RA. In the OA group, however, plasma HA levels were found to correlate with an objective functional capacity score and with an articular index based on the total amount of cartilage in involved joints. In a retrospective longitudinal study of 6 patients with RA, plasma levels of HA did not show a significant correlation with plasma levels of elastase or with the erythrocyte sedimentation rate. These data support in part the contention that plasma HA may be unique as a marker, in that it may be a reflection of synovial involvement and inflammation, rather than only of inflammation, in arthritis.

John P. Huff

Papers

Elevated plasma levels of hyaluronate in patients with osteoarthritis and rheumatoid arthritis.