Extreme obesity due to impaired leptin signaling in mice does not cause knee osteoarthritis

Abstract

Objective: To test the hypothesis that obesity resulting from deletion of the leptin gene or the leptin receptor gene results in increased knee osteoarthritis (OA), systemic inflammation, and altered subchondral bone morphology.

Methods: Leptin-deficient (ob/ob) and leptin receptor-deficient (db/db) female mice compared with wild-type mice were studied, to document knee OA via histopathology. The levels of serum proinflammatory and antiinflammatory cytokines were measured using a multiplex bead immunoassay. Cortical and trabecular subchondral bone changes were documented by microfocal computed tomography, and body composition was quantified by dual x-ray absorptiometry.

Results: Adiposity was increased by approximately 10-fold in ob/ob and db/db mice compared with controls, but it was not associated with an increased incidence of knee OA. Serum cytokine levels were unchanged in ob/ob and db/db mice relative to controls, except for the level of cytokine-induced neutrophil chemoattractant (keratinocyte chemoattractant; murine analog of interleukin-8), which was elevated. Leptin impairment was associated with reduced subchondral bone thickness and increased relative trabecular bone volume in the tibial epiphysis.

Conclusion: Extreme obesity due to impaired leptin signaling induced alterations in subchondral bone morphology without increasing the incidence of knee OA. Systemic inflammatory cytokine levels remained largely unchanged in ob/ob and db/db mice. These findings suggest that body fat, in and of itself, may not be a risk factor for joint degeneration, because adiposity in the absence of leptin signaling is insufficient to induce systemic inflammation and knee OA in female C57BL/6J mice. These results imply a pleiotropic role of leptin in the development of OA by regulating both the skeletal and immune systems.

Figure 1

Histological sagittal sections of knee joints for 44-wk old WT (A, B, C), db/db (D, E, F), and ob/ob (G, H, I) female mice. Higher magnification images are of the central regions of the medial femoral condyle (B, E, H) and tibial plateau (C, F, I). Arrows show examples of lipid deposits in the inter-trabecular region of the epiphysis. Sections are stained with S afranin-O, fast green, and hematoxylin. Bars = 100 μm.

Figure 2

Modified Mankin score of histological changes in the articular cartilage by location in the knee joint of leptin intact (WT) and leptin-impaired (db/db, ob/ob) mice. Values = mean ± SEM.

Figure 3

Sub chondral bone thickness by location in the knee joint of leptin intact (WT) and leptin-impaired (db/db, ob/ob) mice. Values = mean ± SEM.