This cross-sectional study is the first, to our knowledge, to describe the associations between leptin, IL-6, body composition, and hip OA in older adults. We found that serum leptin levels in both sexes and serum IL-6 levels in women were positively associated with hip JSN, but not with osteophytes. The associations were in part dependent on each other, but independent of potential confounders, including age, sex, and BMI. Furthermore, we found that the associations in women between hip JSN and BMI, fat mass, and WHR were dependent on serum leptin levels, but not on serum IL-6 levels.
Emerging evidence suggests that leptin may play a role in knee OA. Chondrocytes possess functional leptin receptors, and low levels of leptin can promote chondrocyte proliferation [35
] and proteoglycan synthesis [37
]. However, overproduction of leptin can increase chondrocyte production of IL-1β and matrix metalloproteinases (MMPs) [23
], and in conjunction with IL-1 or interferon (IFN)-γ, induce nitric oxide synthase (NOS) [38
], which accelerates cartilage degradation. Leptin can be produced within the knee joint [16
], and concentrations of leptin in synovial fluid have been observed to be similar to or even higher than those in serum [23
], suggesting leptin may have a local influence on the joint. However, leptin may also contribute to cartilage destruction through a systemic effect, as suggested by our previous study, negatively associating serum leptin levels with knee cartilage volume [14
], and as well as studies showing that BMI was associated with leptin concentrations in synovial fluid [16
], and that leptin-deficient mice were less likely to have obesity-induced cartilage degeneration [41
]. The results of this present study suggest that hip OA may be affected by leptin in a similar manner; however, its association with the hip appeared stronger than that we had previously found for the knees, because the significant associations in the hips were able to be detected by traditional radiographic assessments, but those in the knees were detected only by the more-sensitive magnetic resonance imaging technique [14
]. This may also reflect that radiographic JSN is a more sensitive measure for the hip than for the knee. Although no equivalent studies exist with which directly to compare ours, recent clinical studies in the knee tend to support our results. Regarding levels of leptin in knee synovial fluid, Ku et al
] reported a positive relation between leptin levels and radiographic severity of OA in a mixed group of 52 subjects, and Gandhi et al
] found that the ratio of adiponectin to leptin was negatively associated with knee pain among a mixed group of 60 subjects. In our results, it is not surprising that the association between OA and leptin decreased somewhat in magnitude after adjustment for IL-6, because leptin belongs structurally to the IL-6 family, and their serum levels were weakly related to each other in this sample.
Inflammation has been implicated in the pathogenesis of OA. Although the literature on hip synovitis is scarce, knee OA has been associated with increased levels of proinflammatory cytokines, such as IL-6, TNF (tumor necrosis factor)-α, and IL-1β in synovial fluid [44
], and our recent study suggested that serum levels of both IL-6 and TNF-α were associated with knee cartilage loss [47
]. Data from the Chingford study also reported that circulating IL-6, but not TNF-α, was associated with OA progression among women [30
]. TNF-α and IL-1α can induce IL-6 production by synovial fibroblasts in the knee [48
] and promote the catabolic effects of IL-6 on cartilage [49
]; however, in vitro
evidence suggests that IL-6 may reduce cartilage degeneration through inhibition of IL-1 and metalloproteinases [27
] and promoting production of collagen II synthesis by chondrocytes [50
], suggesting that IL-6 may also have beneficial effects on cartilage. Currently, no reports describe associations between hip OA severity and systemic levels of IL-6. In this study, we found that serum IL-6 was associated with hip JSN in women but not in men. This is consistent with the finding that IL-6 was cross-sectionally associated with knee ROA collapsed to 3 grades with a large sample size [30
], suggesting that IL-6 also plays a detrimental role in hip OA in women. The reasons for this sex difference are unclear; however, it may reflect the influences of sex hormones in older women. In the absence of estrogen, IL-6 appears to be an upregulator of bone catabolism, leading to osteoporosis or fracture or both [31
], although the relevance of this to hip OA is not known. Additionally, the lower sample size in the stratified analysis may have precluded the detection of a more-modest positive association between IL-6 and hip JSN in men.
Whereas mechanical loading has been suggested as an intermediary between obesity and OA in the knee and hips [52
], it may not always be a contributing factor, especially in non-weight-bearing joints such as the hand [7
]. Consistent with a recent report by Wang et al
], we found that BMI, WHR, body fat, and trunk fat were all significantly associated with hip JSN in women only; in contrast, nontrunk fat was not associated with hip JSN. This suggests that metabolic mechanisms are a possible alternative or complementary causative pathway between obesity and OA, at least for women. Indeed, we found that the positive associations between anthropometric variables and OA were largely dependent on leptin (but not IL-6), suggesting that obesity may cause cartilage damage systemically through production of leptin in adipose tissue in females. The lack of a significant association between body-fat measures and hip JSN among men may be due to modest sample size, and may also reflect a sex difference in the effect of obesity on hip OA. This is in contrast with the finding that leptin levels were significantly associated with axial JSN in men. However, leptin can be derived from nonadipose tissue, as discussed earlier, and non-fat-derived leptin can play a role in the etiology of hip OA in men. IL-6 was weakly associated with leptin and also associated with trunk and total fat ratios in our data, but did not mediate the effect of any of these fat measures on JSN. Taken together, these results suggest that leptin, rather than IL-6, is a key adipose factor involved in hip-cartilage damage. This distinction may be weaker in knee OA, in which IL-6 and leptin from the infrapatellar fat pad, with potential paracrine roles, have been shown to be expressed in greater and lesser proportions, respectively, than in thigh subcutaneous adipose tissue [54
]. Any leptin-mediated effects of obesity may be complemented by a mechanical loading effect in the superior compartment, as suggested by the fact that the consistent associations between obesity measures and JSN in this compartment remained positive after adjustment for leptin. It is unknown whether mechanical loading can induce the expression of leptin within the joint, as has been shown for IL-6 [29
]; such an effect, if any, could explain in part the leptin dependence of the associations between measures of adiposity and hip OA we report in the current study.
This study has several potential limitations. First, the modest sample size in this study could impede our discovery of less-strong associations; larger sample size is required to determine whether the insignificant results were false negative. This may explain why previous reports suggested that both leptin and IL-6 are highly expressed in osteophytes [16
], yet we were unable to describe any associations between osteophytes and serum levels of either. Although our results are in part corroborated by published knee OA literature, we emphasize that the restriction of sample size as well as modest reliability for radiographic measures may influence the interpretation; replication of these findings within other groups of subjects is recommended.
Second, a modest response rate (57%) may have introduced selection bias into our sample. However, no significant differences were present in age, gender, and BMI between those who responded and those who did not. Whereas the sample contained subjects with some diseases, the results were largely unchanged when the analyses were adjusted for disease status or when these subjects were excluded. We measured serum total leptin levels rather than free or bound leptin levels, and the latter may have stronger associations with outcome measures; however, total leptin and free or bound leptin have similar patterns in terms of associations with body composition and gender [56
Last, our study is of cross-sectional design, and the causative relation must be confirmed by future longitudinal studies.