**5. Soy, leptin, and OA**

Leptin is of particular interest in the pathology of OA, as the severity of OA is associated with both weight and BMI [67, 68], and leptin is generally elevated in

obese individuals [69]. Leptin is a hormone secreted by adipocytes and is involved with energy homeostasis, namely through its ability to cross the blood brain barrier to decrease orexigenic neuropeptides and increase anorexigenic neuropeptides [70]. In healthy individuals, leptin is secreted in proportion adipose tissue and energy intake [71]. Leptin is generally thought of as a satiety hormone, although many obese individuals have "leptin resistance" [72] where the secretion of leptin in these individuals does not suppress appetite or lead to reduced energy intake.

The role of leptin may extend beyond energy homeostasis. BMI and plasma leptin levels in OA patients correlate positively [70]. Plasma leptin concentrations have also been found to be 3 times higher in premenopausal women than men [73]. Bao et al. [74] found that injecting the knee with leptin caused significant degradation of the cartilage. Additionally, leptin taken from the synovial joint has been found to be higher than plasma leptin concentrations [75].

Results from our research group, corroborates previous findings [76]. In this study, we examined the relationship between serum and synovial fluid concentrations of leptin in both males and females with varying degrees of OA. Serum and synovial fluid samples were obtained from 20 men (mean age = 68.4 ± 10.8 years) and 20 women (mean age = 61.6 ± 12.4 years) with varying degrees of OA who underwent arthroscopic or total knee replacement surgery. We found that leptin concentrations in both the serum and synovial fluid of patients with knee OA increased according to disease severity. That is, as the level of OA became more severe, the leptin concentration also increased, in both men (**Figure 3A**) and women (**Figure 3B**). We also found a significant correlation between serum and synovial fluid leptin concentration and BMI in both men (**Figure 4A** and **B**) and women (**Figure 5A** and **B**) with OA. These findings indicate that leptin may in part play a role in the increased risk of OA related to obesity.

The mechanism by which leptin may contribute to the pathophysiology of OA is likely due to its place in the cytokine family [72]. Leptin may trigger immune responses by increasing the expression of adhesion molecules, likely through a pro-inflammatory cytokine pathway [77]. Additionally, mice without a working leptin gene (ob/ob) demonstrated decreased secretion of inflammatory cytokines, while the administration of leptin to these mice restored inflammatory secretions [78]. Additionally, leptin receptors are present in the cartilage suggesting a direct action on this tissue. There is evidence [79] that leptin stimulates inflammatory markers Interlukin-6 (IL-6), Interlukin-8 (IL-8), nitric oxide, Interlukin-1 β (IL-1β), Tumor Necrosis Factor-alpha (TNFα), COX2, and PGE 2 in the joint thereby contributing to cartilage matrix breakdown.

Because of isoflavones' role in inflammation, the negative action of excess leptin levels on cartilage may be suppressed by isoflavones. For example, rats fed a high fat

#### **Figure 3.**

*The relationship between serum and synovial fluid concentrations of leptin and severity of OA in both men (A) and women (B).*

**31**

**6. Soy and OA**

**Figure 4.**

**Figure 5.**

cartilage metabolism.

*Evidence for the Effectiveness of Soy in Aging and Improving Quality of Life*

soy diet, or regular soy diet, were found to have lower serum leptin concentrations than those fed a high fat casein, or regular fat casein diet [80]. Their study [80] also found that the expression of inflammatory genes decreased along with the expression of leptin. Niwa et al. [81] also found that soy isoflavones decreased leptin secretion in the adipocytes of mice, and a study by Llaneza et al. [82] found that the consumption of 200 mg of soy isoflavone extract in postmenopausal women resulted in decreased leptin levels, as well as TNFα. Another study in overweight and obese subjects found that after 12 weeks of black soy peptide supplementation,

*The correlation between serum (A) and synovial fluid (B) leptin concentration and BMI in women with OA.*

*The correlation between serum (A) and synovial fluid (B) leptin concentration and BMI in men with OA.*

serum leptin concentrations were significantly reduced from baseline [83].

OA, halting its progression, and improving the QOL of individuals affected.

The main soy isoflavones include genistein, daidzein, and glycetine [84]. Genistein is structurally similar to ipriflavone [84], a synthetic isoflavone. SERMs such as tamoxifen [85] and ipriflavone [86] have both been shown to influence cartilage metabolism and reduce or alleviate the symptoms associated with OA. Therefore, it is conceivable to also expect that genistein similarly influences

Our *in vitro* study [87] found that genistein had the capacity to reduce inflammation in human chondrocytes. Indeed, in chondrocytes treated with LPS to induce inflammation, genistein significantly decreased COX-2 production (**Figure 6**), but

These studies and our observations so far suggest that soy and its isoflavones are likely very efficacious in alleviating pain associated with OA and its symptoms, in part due to its ability to decrease inflammatory responses. Soy's ability to mediate leptin and inflammatory immune responses may also be integral in both preventing

*DOI: http://dx.doi.org/10.5772/intechopen.85664*

*Evidence for the Effectiveness of Soy in Aging and Improving Quality of Life DOI: http://dx.doi.org/10.5772/intechopen.85664*

**Figure 4.**

*The correlation between serum (A) and synovial fluid (B) leptin concentration and BMI in men with OA.*

**Figure 5.** *The correlation between serum (A) and synovial fluid (B) leptin concentration and BMI in women with OA.*

soy diet, or regular soy diet, were found to have lower serum leptin concentrations than those fed a high fat casein, or regular fat casein diet [80]. Their study [80] also found that the expression of inflammatory genes decreased along with the expression of leptin. Niwa et al. [81] also found that soy isoflavones decreased leptin secretion in the adipocytes of mice, and a study by Llaneza et al. [82] found that the consumption of 200 mg of soy isoflavone extract in postmenopausal women resulted in decreased leptin levels, as well as TNFα. Another study in overweight and obese subjects found that after 12 weeks of black soy peptide supplementation, serum leptin concentrations were significantly reduced from baseline [83].

These studies and our observations so far suggest that soy and its isoflavones are likely very efficacious in alleviating pain associated with OA and its symptoms, in part due to its ability to decrease inflammatory responses. Soy's ability to mediate leptin and inflammatory immune responses may also be integral in both preventing OA, halting its progression, and improving the QOL of individuals affected.
