br Methods br Results br Discussion Autotaxin has been

Methods
Results
Discussion Autotaxin has been shown to have effects on major cell types implicated in OA, notably chondrocytes, osteoblasts, osteoclasts, and synoviocytes, through its enzymatic product LPA [20]. However, a paucity of research exists on the involvement of autotaxin in OA. Fibroblast-like synoviocytes from RA patients expressed higher concentrations of autotaxin than healthy and osteoarthritic cells, and were induced by tumor necrosis factor, but interestingly down regulated by interleukin (IL)-4, IL-1β, and interferon-γ [15], [21], [22], cytokines known to be involved in the pathogenesis of OA. Notwithstanding, synovitis, which is common in the early stages of OA, decreases with disease progression, and therefore proinflammatory cytokines may have less of a suppressive effect on autotaxin expression in the later stages of OA, which would support our present results of increasing autotaxin in later stages of OA. It should certainly be noted that autotaxin does not have direct effects on cellular activity; instead it is the bioactive phospholipid LPA which synthesizes and influences the behavior of NS 1619 through the membrane-bound receptors LPA1–6. Circulating autotaxin concentrations and autotaxin activity positively correlated with LPA concentrations [23], [24], thus autotaxin concentrations are representative of LPA. Miyabe et al. demonstrated the involvement of LPA/LPA1 signaling in RA [25]. They showed that LPA1 was expressed extensively in RA synovium samples, significantly more so than in OA samples. Furthermore, they found that LPA was critical for the migration of macrophages in inflamed arthritic tissues, in addition to osteoclastogenesis. Furthermore, LPA can regulate bone remodeling through the suppression of osteoclast differentiation and activity [26] and can stimulate chondrocyte proliferation [27], [28], maturation, and is protective against chondrocyte apoptosis [28], all of which are advantageous in OA by combating the deterioration of cartilage. However, LPA also increased the angiogenic potential of human chondrocytes in vitro by increasing the expression of angiogenic factors including IL-8, MMP-13, and vascular endothelial growth factor (VEGF) via Gi/NF-κB signaling [29]. Likewise, osteoblasts have been observed to increase IL-6 and IL-8 synthesis following exposure to LPA [30]. We have previously found VEGF and IL-8 concentrations to be increased in OA patients [31], [32]. Angiogenesis weakens the structure of cartilage and allows the infiltration of sensory nerves leading to increased pain [33]. Taken together, this may further explain why we observed worse severity of disease in patients with higher autotaxin concentrations. The findings of this study suggest the continued involvement of autotaxin, and consequently its product LPA, in the pathogenesis and progression of knee OA. As such, autotaxin may be a possible therapeutic target in the future. Albeit, due to the myriad of often conflicting effects LPA has on different tissues, direct and general inhibition of autotaxin may prove detrimental within the joint as well as elsewhere in the body. Instead, the targeted interference of cell-type specific receptors or alteration processes which result from autotaxin may be more ameliorating. Orosa et al. have shown the effectiveness of an LPA1 receptor antagonist (Ki16425) in the treatment of RA in mice models [34]. The inhibition led to a reduction in disease severity through altering osteoclast and osteoblast differentiation. But interestingly, LPA1 inhibition did not prevent bone loss in osteoporotic murine models [35]. The search for biochemical markers in OA has been ongoing for a number of years now, but hitherto, an individual marker with unambiguous and clinically significant outcomes has yet to be identified to the point of widespread clinical application [36]. Instead, greater statistical power can be achieved by utilizing a cluster of biomarkers, including cartilage degradation products, bone metabolism markers, and various cytokines. More studies on the investigation of other inflammatory biomarkers (such as IL-1 and IL-6) in local tissues, in relation to their synovial and circulating concentrations could provide useful information on the pathogenic role of autotaxin in OA.