Increase in osteoclastogenesis in an obese Otsuka Long-Evans Tokushima fatty rat model.

In the present study, the effects of obesity on bone metabolism were investigated using a hyperphagic and obese rat model, the Otsuka Long­Evans Tokushima fatty (OLETF) rat, which exhibits normal glycemic control at 8 weeks of age. Body weight, food intake, fat mass, markers of bone resorption, the activities of tartrate­resistant acid phosphatase (TRAP) and cathepsin K, the number of osteoclasts in the proximal tibia, and the serum C­terminal crosslinking telopeptide level were higher in OLETF rats than those in control rats (Long­Evans Tokushima Otsuka; LETO). However, no differences in markers of bone formation, alkaline phosphatase activity, the number of osteoblasts in the proximal tibia or the serum osteocalcin level were observed. mRNA and protein levels of c­fms, receptor for activation of nuclear factor­κB (RANK), RANK ligand (RANKL), TRAP and cathepsin K were significantly increased in OLETF rats, although those levels of macrophage colony­stimulating factor (M­CSF) and osteoprotegerin (OPG) were similar to those in LETO rats. The level of serum tumor necrosis factor α (TNFα), and that of TNFα mRNA in bone, increased in association with the activation of NFκB. Furthermore, a frequency analysis and a colony formation assay respectively showed that the number of osteoclast precursors and the number of colony­forming cells induced by M­CSF each increased in OLETF rats compared with the control group. These results suggested that hyperphagia­induced obesity with normal glycemic control induces the upregulation of osteoclastogenesis that is associated with an increase in the expression of c­fms, RANK and RANKL, which is induced by TNFα, via the activation of NFκB.