Current Molecular Pharmacology - Volume 5, Issue 2, 2012

Intermittent parathyroid hormone (iPTH) is the only FDA-approved therapy for bone loss due to conditions such as osteoporosis that increases bone formation by osteoblasts; all other therapies approved for osteoporosis block bone resorption by osteoclasts. The anabolic effects of iPTH are likely due to a combination of multiple mechanisms, including induction of immediate-early genes, increased expression and/or activity of ess Read More

This review focuses on the mechanisms by which PTH stimulates both osteoblast and osteoclast function, emphasizing the critical role that IGF-I plays in these processes. After reviewing the current literature on the skeletal actions of PTH and the modulation of IGF action on bone by the different IGF-binding proteins, the review then examines studies from mouse models in which IGF-I or its receptor have been selectively Read More

The insulin-like growth factors (IGFs) are the most abundant growth factors stored in bone and produced by osteoblasts. IGF-I is an important regulator of osteoblast function and required for optimal bone development and maintenance. IGF-I can act in an endocrine, paracrine or autocrine manner and is regulated by a family of six IGF binding proteins (IGFBPs). The IGFBPs are often found bound to IGF-I in the circulation or Read More

Bone morphogenetic proteins (BMPs) were discovered in 1965 as potent inducers of ectopic bone formation when implanted subcutaneously. BMP2, BMP4, BMP6, and BMP7 are osteoinductive, and BMP2 and BMP7 are currently approved for clinical applications such as bone fracture healing and spine surgery. Although BMPs’ role in bone formation is well known, the current clinical data supporting their effectiveness a Read More

Normal bone homeostasis is the result of a cross-talk between the anabolic axis (osteoblast differentiation) and catabolic axis (osteoclast remodeling). A disruption of this tightly regulated relationship leads to imbalanced bone turnover which ultimately results in diseases of the skeleton. Given that the majority of disease states are characterized by an inadequate renewal of osteoblasts, and the canonical wingles Read More

Prostaglandin E2 is known to be a potent metabolite in bone biology. Its effects are mediated via four receptor subtypes with different properties, effects and mechanisms of action. The EP2 and EP4 receptors have been extensively investigated as bone anabolic therapy targets in the literature. The aim of this review was to analyse the available evidence supporting the use of selective agonists for those receptors for a Read More

With a rise in the aging population, the global osteoporosis market represents a major unmet need and one of the greatest challenges for the pharmaceutical companies. Currently bisphosphonates constitute the mainstay antiosteoporotic treatment. They inhibit osteoclast-dependent bone resorption, and substantially reduce the risk of vertebral and non-vertebral fractures. However, bisphosphonates are only marginally eff Read More

Osteoporosis is a major public health problem for adults above 55 years of age, which leads to an increase in bone fragility. Last decade has witnessed remarkable advances in molecular biology and genetics that led to detailed understanding of the bone remodeling cycle and new therapeutic targets for its treatment have emerged. Thus, besides classical approach (vitamin D and calcium administration, bisphospho Read More

Current antiresorptive therapies not only prevent bone loss by decreasing osteoclastic bone resorption but also inhibit bone formation. Dual anabolic antiresorptive agents may be required to cure severe osteoporosis by preventing further bone loss and increasing bone mass to normal levels. Recent studies have demonstrated that activin signaling plays a crucial role in the skeleton. Activins, like other TGF-β superfamily Read More

From a nutritional point of view, several factors are involved in ensuring optimal bone health. The most documented of these are calcium and vitamin D. However, it is now well acknowledged that some phytochemicals, also known as phytonutrients, which are plant-based compounds that are present in our daily diet, can positively regulate a number of physiological functions in mammalian systems involved in chronic disea Read More

Chronically-elevated plasma lipid concentrations, particularly when combined with high glucose, elicit a plethora of effects that cause the progressive deterioration of insulin sensitivity and ultimately cellular malfunction or death. This review addresses how metabolic abnormalities in white adipose tissue leading to excessive lipid or abnormal adipokine release can be modified by PPARγ activation. It also discusses the Read More

Cardiometabolic syndrome is a mixture of interrelated risk factors predisposing individuals to elevated risk of atherosclerotic cardiovascular disease and type 2 diabetes mellitus. Nuclear receptors, specifically peroxisome proliferator-activated receptors (PPARs), were identified to play a pivotal role in the regulation of metabolic homeostasis. However, with rosiglitazone currently under intense scrutiny great concerns have arisen Read More

Peroxisome proliferator-activated receptor (PPAR)γ, a nuclear hormone receptor, is activated by its agonists including anti-diabetic thiazolidinediones, and has recently been reported to exert beneficial effects in the vasculature independently of its anti-diabetic effects. We here discuss our recent findings on the beneficial pleiotropic effects of PPARγ agonists. PPARγ agonists have been shown to lower blood press Read More

PPAR agonists represent a heterogeneous group of compounds that have been used in the treatment of cardiovascular and metabolic diseases for over thirty years. While the primary indications for PPAR agonist therapy focus on hyperlipidemia and diabetes, there is a growing body of pre-clinical data that suggests they may be beneficial in the treatment of heart failure; a disease marked by abnormal myocardial metabolis Read More

PPARγ-modulators, a class of anti-diabetic drugs as represented by thiazolidinediones (TZD), have been associated with cardiovascular risks in type-2 diabetes in humans but a similar liability has not been demonstrated in preclinical models. This gap between clinical and preclinical observations may reflect the lack of a translational model for cardiac safety assessment because preclinical efficacy for glycemic control for PPARγ- Read More

Peroxisome proliferator-activated receptor (PPAR) is involved in the pathology of numerous diseases including obesity, diabetes, and atherosclerosis, because of its role in decreasing insulin resistance and inflammation. Type 2 diabetes mellitus and obesity are the most frequent endocrine-metabolic diseases and their pathogenic basis are characterized by insulin resistance and insulin secretion defects that can b Read More

Peroxisome Proliferator-Activated Receptor γ (PPARγ), originally described as a transcription factor for genes of carbohydrate and lipid metabolism, has been more recently studied in the context of cardiovascular pathophysiology. Here, we review the available data on PPARγ ligands as modulator of vascular tone. PPARγ ligands include: thiazolidinediones (used in the treatment of type 2 diabetes mellitus), glitazars (bind Read More

Autosomal dominant polycystic kidney disease (ADPKD) is the most common of the monogenic disorders and is characterized by bilateral renal cysts; cysts in other organs including liver, pancreas, spleen, testis and ovary; vascular abnormalities including intracranial aneurysms and subarachnoid hemorrhage; and cardiac disorders such as left ventricular hypertrophy (LVH), mitral valve regurgitation, mitral valve prol Read More