Regulation of osteoblast/osteoclast cross-talk by factors potentially leading to a positive bone balance : evaluation of GH, CGRP and phenylcarboxylic acid derivatives

In this study it was evaluated the role of growth hormone (GH), calcitonin gene-related peptide (CGRP) and of new molecules of synthesis in the regulation of biomolecular mechanisms involved in the process of bone remodeling. The effect of GH and CGRP in the expression and secretion of osteoprotegerin (OPG) was evaluated in primary cultures of human osteoblast-like cells (hOB). These cells showed to express both a specific GH receptor and a CGRP receptor. GH (4.5x10-11M) induced an enhancement of OPG in a specific and receptor mediated way without the involvement of IGF-I. On the contrary CGRP (1.08x10-10M) inhibited OPG production. This effect was mediated by the CGRP induced stimulation of cAMP and involvement of phosphokinase A. Since OPG secretion was reduced, conditioned media from CGRP treated hOB, stimulated osteoclast formation from human peripheral blood mononuclear cells compared to conditioned media of untreated cells. Thus suggesting that CGRP exerts its anabolic effects on bone by modulating the fine balance of bone cell coupling. A series of novel biphenylcarboxylic acid derivatives, called ABD compounds, were tested in primary cultures of murine osteoblasts, macrophages and osteoclasts derived from mouse bone marrow. All compounds showed antiosteogenic effect mediated by inhibition of RANKL induced intracellular signalling (NFkB pathway), and by activation of p38/JNK proapoptotic pathway.