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 Long-Evans 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 tartrate-resistant acid phosphatase (TRAP) and cathepsin K, the number of osteoclasts in the proximal tibia, and the serum C-terminal crosslinking telopeptide level were higher in OLETF rats than those in control rats (Long-Evans 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 c-fms, receptor for activation of nuclear factor-kappa B (RANK), RANK ligand (RANKL), TRAP and cathepsin K were significantly increased in OLETF rats, although those levels of macrophage colony-stimulating factor (M-CSF) and osteoprotegerin (OPG) were similar to those in LETO rats. The level of serum tumor necrosis factor alpha (TNF alpha), and that of TNFa mRNA in bone, increased in association with the activation of NF kappa B. Furthermore, a frequency analysis and a colony formation assay respectively showed that the number of osteoclast precursors and the number of colony-forming cells induced by M-CSF each increased in OLETF rats compared with the control group. These results suggested that hyperphagia-induced obesity with normal glycemic control induces the upregulation of osteoclastogenesis that is associated with an increase in the expression of c-fms, RANK and RANKL, which is induced by TNFa, via the activation of NF kappa B.