Griffin Timothy M, Huebner Janet L, Kraus Virginia B, Guilak Farshid
Duke University Medical Center, Durham, North Carolina 27710, USA.
Arthritis Rheum. 2009 Oct;60(10):2935-44. doi: 10.1002/art.24854.
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.
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.
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.
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.
验证以下假说，即因瘦素基因或瘦素受体基因缺失导致的肥胖会致使膝关节骨关节炎（OA）增加、全身性炎症加剧以及软骨下骨形态改变。
研究了与野生型小鼠相比的瘦素缺乏型（ob/ob）和瘦素受体缺乏型（db/db）雌性小鼠，通过组织病理学记录膝关节OA情况。使用多重珠免疫测定法测量血清促炎和抗炎细胞因子水平。通过微焦点计算机断层扫描记录皮质和小梁软骨下骨的变化，并通过双能X线吸收法对身体成分进行量化。
与对照组相比，ob/ob和db/db小鼠的肥胖程度增加了约10倍，但这与膝关节OA发病率的增加无关。与对照组相比，ob/ob和db/db小鼠的血清细胞因子水平没有变化，除了细胞因子诱导的中性粒细胞趋化因子（角质形成细胞趋化因子；白细胞介素-8的小鼠类似物）水平升高。瘦素功能受损与胫骨骨骺软骨下骨厚度降低和相对小梁骨体积增加有关。
由于瘦素信号受损导致的极度肥胖会引起软骨下骨形态改变，但不会增加膝关节OA的发病率。ob/ob和db/db小鼠的全身性炎症细胞因子水平在很大程度上保持不变。这些发现表明，身体脂肪本身可能不是关节退变的危险因素，因为在缺乏瘦素信号的情况下，肥胖不足以在雌性C57BL/6J小鼠中诱导全身性炎症和膝关节OA。这些结果暗示了瘦素在OA发展过程中通过调节骨骼和免疫系统发挥多效性作用。
