[Frontiers in Bioscience 3, d769-780, August 1, 1998]
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G-PROTEIN COUPLED RECEPTORS IN BONE

Wayne B. Bowler1, James A. Gallagher and Graeme Bilbe2

1 Human Bone Cell Research Group, Department of Human Anatomy and Cell Biology, University of Liverpool, England, L69 3GE 2 Novartis Pharma A.G., Postfach, K681.4.43, CH-4002 Basel, Switzerland

Received 1/16/98 Accepted 2/17/98

2. INTRODUCTION

Bone is a highly specialized tissue which undergoes cellular activity throughout life This is evident initially in the processes of growth and modeling which give rise to the mature skeleton. When longitudinal growth has ceased, cellular activity results in the processes of remodeling, renewed modeling and repair, all essential for the homeostasis of the mature skeleton. The principal cellular functions are bone formation, brought about by osteoblasts, and bone resorption, which is brought about by osteoclasts. The genesis, differentiation and activities of osteoblasts and osteoclasts are regulated by endocrine and paracrine factors which interact with specific receptors in cells (For review see (21)).

The G-protein coupled receptors which constitute the most important families of receptors in bone, are characterized by their ability to couple to catalytic heterotrimeric G-proteins, which through phosphorylation on serine/threonine residues, activate intracellular signalling cascades. Many important calciotrophic hormones including PTH and calcitonin, and local effectors such as PTHrP, ATP and prostaglandins initiate profound autocrine and paracrine events through the activation of G-protein-coupled receptors . As such this family of receptors provide the most propitious targets for pharmacological intervention in diseases of bone loss including osteoporosis.

The huge diversity of downstream cellular responses initiated upon G-protein coupled receptor-agonist binding is facilitated by a number of events. Alternate splicing of receptor mRNA can generate multiple subtypes that differentially couple to one of the many characterized G-proteins, thereby activating specific intracellular cascades. The coupling specificity of receptor isoforms is the mechanism employed by locally released prostaglandins to differentially regulate osteoblast function. Differentiation stage specificity of signal transduction can occur through modulation of receptor-G-protein subtype coupling. Thus, the developmental status of bone cells can determine PTH receptor/G-protein interaction and therefore the activation of intracellular signaling cascades. Alternatively the interaction of multiple agonists provides a further layer of signaling diversity. Indeed, the interaction of local factors with those classically described hormones, has been forwarded as a means of localizing systemic responses in bone. In this review we describe in detail the molecular, and functional properties of the currently known G-protein coupled receptors expressed by osteoblasts and osteoclasts, and highlight the signaling diversity utilized by these receptors to maximize their functional impact.