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 telo- peptide 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 phospha- tase 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-κB (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 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 colony-forming cells induced by M-CSF each increased in OLETF rats compared with the control group. These results suggested that hyper- phagia-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 TNFα, via the activation of NFκB.