In this large community-based sample, we identified small but significant increases in the presence, laterality and severity of knee rOA with increasing levels of whole blood Pb. A similar pattern of findings was seen for sxOA, although it was not statistically significant, likely because of smaller numbers of participants with sxOA outcomes in the sample. The associations were strongest for the most severe categories (moderate or severe, or bilateral involvement). While blood Pb levels were affected by demographic factors, being higher in African-Americans than in Caucasians, higher in men than in women, higher in those with lower BMI and higher in those who reported current smoking or current alcohol drinking, the associations with knee rOA remained statistically significant after adjustment for these factors, and no significant interactions between covariates were identified. Interestingly, while lower BMI, smoking and alcohol drinking were all protective factors in the prevalent rOA analysis, and all were associated with higher Pb levels, even after adjustment for these factors, we identified a significant effect of elevated blood Pb level on the presence of rOA. This suggests to us that this ubiquitous environmental toxicant may have a role in knee OA.
The blood Pb levels seen in our study were comparable to those reported in other studies of the health effects of blood Pb levels in nonoccupationally exposed individuals [10
]. These levels are far below the threshold for chelation therapy (50 μg/dl or higher with severe symptoms, or greater than 100 μg/dl with or without symptoms [41
The associations between rOA and whole blood Pb levels could be due to a detrimental effect of Pb on the joints leading to structural damage, or the increased Pb levels could reflect an increased rate of bone turnover in OA leading to increased release of Pb from bone. The associations between blood Pb level and sxOA could be related to modulation of pain perception by Pb itself, given its known neurotoxic effects [42
]. Although we are unable to draw any causal conclusions on the basis of this cross-sectional data analysis, there is support for a potential causative effect of Pb in OA. Pb is locally toxic to bone, and intraarticular Pb, as demonstrated with retained Pb bullets, can lead to arthritis, synovitis and even systemic toxicity [43
]. Mice exposed to Pb have delayed fracture healing and reduced endochondral maturation [31
], suggesting a potential impact of Pb on bone remodeling, a process seen in OA. A study of trace elements in bone found significantly lower Pb concentrations in femoral heads of patients undergoing total hip replacement for OA than in those with hip fracture or in necropsy controls, suggesting release of Pb into the circulation from the remodeling OA bone [45
]. In contrast, a study of articular cartilage and subchondral bone from individuals without bone disease or known Pb exposure showed differential specific accumulation of Pb in the tidemark region [29
]. The tidemark represents the transition between calcified and uncalcified cartilage, an area known to advance, duplicate and develop clefts during the development of OA. These findings suggest that Pb may have a direct effect on the joints in OA beyond the release of Pb into the circulation as a consequence of bone remodeling. It is also possible that early changes in OA lead to the release of Pb from bone, thus aggravating joint damage. A mechanism by which Pb exposure may increase the susceptibility of osteoblasts to environmental toxins has recently been proposed [46
], and it may be that regardless of causality, once the Pb levels are increased, a cycle of increased susceptibility to toxic damage may begin.
Another mechanism by which Pb may contribute to pathology in OA is through nitric oxide (NO), an important mediator of oxidative stress. Chondrocytes have long been known to express inducible nitric oxide synthase (NOS) [47
], and recently a greater role for NO in the pathogenesis of OA has been recognized [48
]. Increased production of NO and associated molecules has been noted in OA joints and specifically in chondrocytes [48
]. Beneficial effects of NO on chondrocytes and the cartilage matrix, mediated through constitutive NOS, as well as negative effects mediated by inducible NOS, have been identified [48
]. Differential effects on pain based on the pathway and local environment where NO is produced have also been found [48
]. Interestingly, and pertinent to the current study, Pb can both increase reactive oxygen species and reduce the availability of NO, thereby increasing potential oxidative stress [52
]. In studies of Pb-induced hypertension, a cycle of increased oxidative stress leading to nuclear factor-κB-mediated inflammation and apoptosis, followed by additional oxidative stress from the released inflammatory mediators and subsequent increased inflammation, has been hypothesized [52
] and is thought to be aggravated by Pb exposure, which contributes to inflammation, apoptosis and reduced NO production [53
]. Increased Pb levels may therefore lead to more severe rOA and more severe symptoms, as seen in the current analysis, by contributing to increased inflammation and oxidative stress mediated through a reduction in NO.
There are some limitations to the current study. Whole blood Pb measurements were used as an economical and readily available biomarker for Pb exposure [54
]. Although specialized X-ray fluorescence techniques to assess bone Pb are considered the "gold standard" for measurement of Pb storage, this procedure is expensive and not widely available [54
]. Since blood Pb levels reflect recent exposure as well as the mobilization of Pb from bone [19
], and since blood Pb level has been associated with all-cause mortality, cardiovascular disease and renal disease [25
], this measure of Pb was used instead. The current study is also limited because of its cross-sectional design, although the potential for future longitudinal studies of Pb in this population exist. The strengths of this study include its community-based biracial sample, large sample size and the availability of high-quality radiographic and symptomatic outcome data gathered in a standard manner.