Current Pharmaceutical Design - Volume 7, Issue 4, 2001

The orphan nuclear receptors FXR and LXR alpha have become challenging targets for the discovery of new therapeutic agents. Bile acids and hydroxysterol intermediates are the respective natural ligands of these two structurally and functionally closely related receptors. Both FXR and LXR alpha are thought to play a major role in the control of cholesterol catabolism by regulating the expression of cholesterol 7alpha-hydroxylase, the rate limiting enzyme of bile acid synthesis. Reverse cholesterol transport might also be affected by FXR and LXR since they control the expression of PLTP and CETP, two proteins involved in the transfer of phospholipid, cholesterol and cholesteryl esters among plasma lipoproteins. A new class of potent synthetic activators of FXR, the 1,1-bisphosphonate esters, has been discovered which up regulate the Intestinal Bile Acid Binding Protein gene (I-BABP) as demonstrated for chenodeoxycholic acid, however there are no known synthetic activators yet identified for LXR alpha. The evaluation of FXR as a potential target for the development of drugs affecting plasma cholesterol can take advantage of the fact that the activators of FXR (farnesol, bile acids and the 1,1-bisphosphonate esters) have been studied in various in vitro and in vivo models. Administration of chenodeoxycholic acid to animals and man did not result in the increase in plasma cholesterol expected from a decrease in cholesterol 7alpha-hydroxylase expression. Like farnesol, the 1,1-bisphosphonate esters increase the rate of degradation of HMGCoA reductase and have the unexpected property of inducing hypocholesterolemia in normal animals. The natural and synthetic FXR agonists trigger differentiation, inhibit cell proliferation and are potent inducers of apoptosis. The 1,1-bisphosphonate ester SR-45023A (Apomine) is presently being developed as an antineoplastic drug.

Research indicates that endurance exercise training has significant effects upon the reproductive endocrine system of humans. Until recently, this effect was thought to be limited primarily to women. However, a growing body of evidence demonstrates that the male reproductive endocrine system is also effected. Specifically, the circulating hormonal levels of testosterone are found to be at low concentrations and, the hypothalamic-pituitary-testicular axis that regulates testosterone production is altered in endurance trained men. The physiological mechanism inducing the lower testosterone is currently unclear but in many respects, these men display hypogonadotropic hypogonadism characteristics. Currently, the time course of the changes in the reproductive endocrine system is unresolved and in need of much furthers scientific investigation. The evidence available, however, suggests that a slowly developing process requiring years of exercise training results in these changes. Potentially, the lowered testosterone levels of the endurance-trained male could disrupt some of their anabolic or androgenic dependent processes. To date, there are only a limited number of findings suggesting that a consistent disruption of testosterone dependent processes occur due to endurance exercise training (e.g., oligo-spermatogenesis). Conversely, the alterations in testosterone concentration brought about by endurance training could have cardiovascular protective effects and thus be beneficial to the health of these men.

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.

Proteomics is a technology platform that is gaining widespread use in drug discovery and drug development programs. Defined as the protein complement of the genome, the proteome is a varied and dynamic repertoire of molecules that in many ways dictates the functional form that is taken by the genome. The importance of proteomics is a direct consequence of the central role that proteins play in establishing the biological phenotype of organisms in healthy and diseased states. Moreover, proteins constitute the vast majority of drug targets against which pharmaceutical drug design processes are initiated. By studying interrelationships between proteins that occur in health and disease and following drug treatment, proteomics contributes important insight that can be used to determine the pathophysiological basis for disease and to study the mechanistic basis for drug action and toxicity. Proteomics is also an effective means to identify biomarkers that have the potential to improve decision making surrounding drug efficacy and safety issues based on data derived from the study of key tissues and the discovery and appropriate utilization of biomarkers.