The actions of hypothermia and PPAR agonists on the differentiation and function of bone cells

It has long been long known that core body temperature declines with age. However, its effect on bone cell function and skeletal homeostasis have been little studied. To investigate this, bone-forming osteoblasts and bone resorbing osteoclasts were exposed to mild hypothermia (35.5oC) and severe hypothermia (34oC). Formation of 'trabecular' bone structures by osteoblasts was reduced by up to 95% in hypothermic cultures, compared to 37oC controls. In addition to reductions in osteoblast cell number, expression of osteocalcin, type I collagen, alkaline phosphatase and Runx2 were also down-regulated in hypothermia. Microarray analysis indicated an initial period of down-regulation of transcripts in hypothermia, followed surprisingly, by up-regulation as cultures progressed. In contrast, formation of osteoclasts showed up to 2-fold stimulation in hypothermia; resorption pit formation was similarly increased. Microarray analysis showed that genes involved in osteoclast formation and cold response were up-regulated in hypothermic cultures. In addition to reductions in core temperature, the elderly have a higher prevalence of type 2 diabetes and hyperlipidaemia. These conditions are independent risk factors in the pathogenesis of osteoporosis; however, drug therapies, namely PPAR agonists, have been reported to affect bone cell function. Thiazolidinediones (rosiglitazone and troglitazone) are PPAR-γ agonists used in the management of type 2 diabetes; fibrates (such as fenofibrate) are PPAR-α agonists used in the treatment of hypertriglyceridaemia. Bone formation by osteogenic cells was inhibited by up to 85% in cultures treated with rosiglitazone, and by 45% in troglitazone or fenofibrate treated cultures. Lipid formation however, increased by 40-70% in these cultures. Expression of Runx2, alkaline phosphatase, osteocalcin and type I collagen were down-regulated, whereas PPAR-γ was up-regulated, in treated cultures. Osteoclast formation and resorptive activity were diminished with fenofibrate treatment, whereas both thiazolidinediones reduced resorptive activity without affecting osteoclast number. These findings raise the possibility that hypothermia or treatment with PPARs could adversely affect bone metabolism in the elderly