Bone Abstracts

Receptor activity modifying proteins (RAMPs 1, 2 and 3) are a class of important accessory proteins that interact and regulate several G-protein coupled receptor (GPCR) activity by finely modulating ligand interaction and in some cases trafficking receptors to cell surface.

Predominant roles of RAMPs include ligand selectivity in receptors for Calcitonin (CT) family of peptides that comprise calcitonin, calcitonin gene related peptide, amylin and Adrenomedullin. Functional receptors to these peptides result from heterodimer formed between a RAMP and CT receptor or calcitonin-like receptor.

To test our hypothesis that altering RAMP expression alters skeletal phenotype; we conducted skeletal analysis of RAMP1/2/3 transgenic mice. We observed that RAMP2 −/− mice are not viable, but heterozygotes exhibit a haploid insufficiency phenotype with aberrant endocrinology and in the skeletons, thinner cortices than WT controls. Whereas, RAMP3 −/− (R3KO) mice had a significant increase in cortical thickness and bone volume.

MicroCT analysis of postnatal day 5 (WT: n=14, R3KO: n=15), 27-day-old mice (WT: n=16, R3KO: n=15), and 8 week old (WT: n=6, R3KO: n=6) mice revealed an age dependent skeletal phenotype with evidence of accelerated skeletal development until 27days of age in the R3 KO mice. Dynamic histomorphometry revealed increased bone apposition rate in the endocorital region of tibia at 8 weeks. Ovariectomy at the age of 12 weeks showed significant increase in trabecular pattern factor and thickness of tibiae of R3 KOs. Primary osteoblast cultures from neonatal calvaria revealed significant increase in total β-catenin in R3 KO cultures.

Our data provides evidence to significant role of R3 in skeletal regulation and suggests that data implicating R3 as an early response gene in WNT stimulation in cancer cells has wider physiological consequences and is an interesting drug target.