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Chondroitin sulfate and glucosamine sulfate exert beneficial effects on the metabolism of in vitro models of cells derived from synovial joints: chondrocytes, synoviocytes and cells from subchondral bone, all of which are involved in osteoarthritis (OA). They increase type II collagen and proteoglycan synthesis in human articular chondrocytes and are able to reduce the production of some pro-inflammatory mediators and proteases, to reduce the cellular death process, and improve the anabolic/catabolic balance of the extracellular cartilage matrix (ECM). Clinical trials have reported a beneficial effect of chondroitin sulfate and glucosamine sulfate on pain and function. The structure-modifying effects of these compounds have been reported and analyzed in recent meta-analyses. The results for knee OA demonstrate a small but significant reduction in the rate of joint space narrowing. Chondroitin sulfate and glucosamine sulphate are recommended by several guidelines from international societies for the management of knee and hip OA, while others do not recommend these products or recommend only under condition. This comprehensive review clarifies the role of these compounds in the therapeutic arsenal for patients with knee OA.

The in-vitro effects of avocado and soybean unsaponifiable residues on neutral metalloproteinase activity, cytokines and prostaglandin E2 (PGE2) production by human articular chondrocytes were investigated. Avocado and soybean unsaponifiable residues were mixed in three ratios: 1:2 (A1S2), 2:1 (A2S1) or 1:1 (A2S2). Freshly isolated human chondrocytes were cultured for 72 h in the absence or presence of interleukin-1beta, (IL-1beta) (17 ng/ml), with or without unsaponifiable residue mixtures at a concentration of 10 microg/ml. A/S unsaponifiable residues were also tested separately at concentrations of 3.3, 6.6 and 10 microg/ml. All A/S unsaponifiable mixtures reduced the spontaneous production of stromelysin, interleukin-6 (IL-6), interleukin-8 (IL-8) and prostaglandin E2 (PGE2) by chrondrocytes. At concentrations of 3.3 and 6.6 microg/ml, A/S residues, tested separately, were potent inhibitors of the production of IL-8 and PGE2. Nevertheless, only avocado residue inhibited IL-6 production at these concentrations. A/S unsaponifiable mixtures had a more pronounced inhibitory effect on cytokine production than avocado or soybean residues added alone. As anticipated, IL-1beta induced a marked release of collagenase, stromelysin, IL-6, IL-8 and PGE2. A/S unsaponifiable mixtures partially reversed the IL-1 effects on chrondrocytes. These findings suggest a potential role for A/S unsaponifiable extracts in mitigating the deleterious effects of IL-1beta: on cartilage.

Cytokines are potent regulators of the chondrocyte functions. Some of them are produced by chondrocytes and interact to regulate cartilage metabolism. In this study, we investigated the production of interleukin-1 beta (IL-1 beta), IL-6, IL-8 and leukemia inhibitory factor (LIF) by human chondrocytes and examined the modulation of their secretion by exogenous cytokines. Human articular chondrocytes were isolated from their extracellular matrix by a triple successive enzymatic digestion of the cartilage. Subsequently, chondrocytes were stimulated by increased amounts of human recombinant cytokines [IL-1 beta, tumour necrosis factor alpha (TNF alpha), IL-8, LIF, IL-6]. IL-1 beta, IL-6, IL-8 and LIF were assayed into culture media and inside cell extracts by specific enzyme amplified sensitivity immunoassays (EASIAs). Under these experimental conditions, we have identified various interactions between cytokines. IL-beta and TNF alpha highly stimulated IL-6, LIF and IL-8 productions. IL-6 decreased IL-8 synthesis and increased LIF production. IL-8 slightly enhanced IL-6 production. Finally, LIF stimulated IL-1 beta, IL-6 and IL-8 productions. Using neutralizing antibodies against IL-1, we demonstrated that the effects of LIF were secondary to the stimulation by LIF of IL-1 beta production by the chondrocytes. In conclusion, chondrocytes secrete a variety of immunocompetent cytokines including IL-1 beta, IL-6, IL-8 and LIF that can interact to regulate chondrocytes metabolism. These results also define new biological activities of LIF and IL-6, and raise questions concerning their role in the pathogenesis of joint diseases.

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