Pharmacological Interference with Transcriptional Control of Osteoblasts A Possible Role for Leptin and Fatty Acids in Maintaining Bone Strength and Body Lean Mass

Jan   O.   Gordeladze; James   E.   Reseland; Christian   A.   Drevon

Abstract

Osteoblasts pass through a sequence of events controlled by hormones and transcriptional factors ensuring proper development of phenotype and functional properties until the osteoblast enter the osteocyte phenotype and/or undergo apo-ptosis. During its life cycle, the osteoblasts proliferate, deposit matrix proteins and mineralize it until they turn into osteocytes believed to constitute a mechanosensor mesh giving feed-back to the osteoblast to initiate bone modeling or remodeling necessary for the making or remaking of proper bone architecture and strength. It appears that several factors common to osteoblast and adipocyte differentiation determine their entry into different functional stages. Such factors are insulin, growth hormone (GH), insulin-like growth factor type I (IGF-I), transforming growth factor beta(TGFbeta), platelet derived growth factor (PDGF), fibroblast growth factor (FGF), cytokines (e.g. interleukins, interferon and tumor necrosis factor alpha (TNFalpha), bone morphogenic proteins (BMPs), glucocorticoids, retinoic acid (RA), prostaglandins and cAMP-elevating hormones. The focus of this article is to review the effects of leptin on bone cells and bone turnover, the peroxisome proliferator-activated receptors (PPARs) in the regulation of bone and fat cell differentiation, hormones and fatty acids on the orchestration of osteoblast and adipocyte derived regulatory signals, and mechanostimulation of bone on the mechanisms by which the above mentioned factors modulate osteoblast and adipocyte function. The hypothesis or concept is that prescription of a certain treatment regimen to correct bone turnover, without attempting to assess how hormonal homeostasis, nutritional factors and physical exercise may interact locally, will remain far from optimal, and may even prove detrimental to the patients health condition.

Keywords: Osteoblasts, Leptin, Insulin-like growth factor type I IGF-I, Cell differentiation, Peroxisome proliferator-activated receptor PPARs, Cytokines, Interleukins, Interferon, Tumor necrosis factor, Glucocorticoids