Disease relevance of Calcr

• Although Amylin +/- mice like Amylin-deficient mice display a low bone mass phenotype and increased bone resorption, Calcr +/- mice display a high bone mass due to an increase in bone formation [1].
• However, unlike sCT, CTR did not induce anorexia and weight loss in rats following sc injection [2].
• F.9 embryonal carcinoma cell calcitonin autocrine system: correlation between immunoreactive calcitonin secretion and calcitonin receptor number [3].

High impact information on Calcr

• Amylin inhibits bone resorption while the calcitonin receptor controls bone formation in vivo [1].
• Calcitonin stimulated all phases of angiogenesis through the calcitonin receptor, but its effect on tube morphogenesis by endothelial cells occurred at the concentration of the Kd of calcitonin receptor [4].
• Using reverse transcription and the polymerase chain reaction to estimate the relative abundance of calcitonin receptor mRNA, a 25-fold accumulation of the splice variant, CR-1a, was observed in embryos between the 1-cell and 8-cell stages [5].
• Such inhibitory effects of EP4-mediated signals on osteoclast function are similar to those that are calcitonin receptor-mediated [6].
• Binding of CT to Vero cells or to ganglioside GM1, a CT receptor, was inhibited in a concentration-dependent manner by HBT and applephenon but not RG-tannin [7].

Chemical compound and disease context of Calcr

• All of the CT receptor-positive cells in control cultures and all of those seen shortly after 1,25-(OH)2D3 addition were mononuclear, despite considerable bone resorption; the majority of CT receptor-positive cells remained mononuclear throughout the incubation period [8].
• Without 1,25-dihydroxy-vitamin D3 [1,25-(OH)2D3], a hormone that induces osteoclastic differentiation in vitro, bone marrow cultures showed very little bone resorption, and only small numbers of CT receptor-positive cells developed [8].
• Though from our studies it would seem reasonably clear that CGRP is weakly agonistic for the calcitonin receptor on the osteoclast to produce effects on bone resorption and plasma calcium, it is still unclear whether the elevation of bone cyclic AMP simply represents an osteoclastic effect or an additional, more important, effect on osteoblasts [9].
• Bone resorption was increased (10(-7) M PGE2 and 10(-6) M PGE1) in association with the increased CTR-positive cell numbers, suggesting that the PG also induced resorptive function [10].
• PGF2 alpha had no significant effect on CTR-positive cell induction or bone resorption [10].

Biological context of Calcr

• Calcitonin receptor and TRAP mRNA levels were determined using semi-quantitative reverse transcription/polymerase chain reaction [11].
• CT (10(-7) M) treatment of 7 day cultures, which had been stimulated to express the osteoclastic phenotype, caused a marked decrease in CTR mRNA expression at 24 h [12].
• Calcitonin-dependent down-regulation of the mouse C1a calcitonin receptor in cells of the osteoclast lineage involves a transcriptional mechanism [13].
• These transfection data confirm the osteoclast specificity of promoter P3 and provide the first evidence that the CTR gene is regulated in a tissue-specific manner by alternative promoter utilization [14].
• In summary, our data show that cholera toxin pretreatment makes calvarial bones insensitive to calcitonin-induced inhibition of bone resorption as a result of an interaction with cholera toxin at the level of calcitonin receptor-linked signal transduction [15].

Anatomical context of Calcr

• The aim of this study was to examine the effects of continuous treatment with CT on the generation of osteoclasts and calcitonin receptor (CTR) expression in mouse bone marrow cultures [11].
• Effects of continuous calcitonin treatment on osteoclast-like cell development and calcitonin receptor expression in mouse bone marrow cultures [11].
• Characterization of amylin and calcitonin receptor binding in the mouse alpha-thyroid-stimulating hormone thyrotroph cell line [16].
• When the 3'UTR of mouse CTR mRNA was labeled by [alpha-(32)P]-uridine 5-triphosphate, interactions were observed between the transcript and several cell extracts, including those from the osteoclast progenitor monocyte/macrophage cell line, RAW 264 [17].
• In neonatal mouse calvaria cultures, CTR mRNA expression was constitutively present and was markedly decreased by 48 h of CT treatment [12].

Associations of Calcr with chemical compounds

• In 1,25-(OH)2D3 treated cultures CTR mRNA was detectable in nonadherent cells on day 3 and in adherent cells on day 5 and thereafter [12].
• The CTR mRNA transcript contains several adenylate/uridylate (AU)-rich destabilizing elements in the 3' untranslated region (3'UTR) [17].
• Consistent with these results, treatment of OCLs with sCT greatly decreased the expression of CTR messenger RNA, whereas no significant effect was observed on the tartrate-resistant acid phosphatase messenger RNA expression, a marker of resorptive capacity of osteoclasts [18].
• Moreover, competitive RT-PCR analysis revealed that 1-h treatment with CT reduced the level of CTR heterogeneous nuclear RNA to 10% in a cycloheximide-independent manner [13].
• From a Scatchard plot analysis, DEX enhanced CTR number (212 +/- 64%) with a minimal change in the affinity to sCT [19].

Regulatory relationships of Calcr

• These results suggest that CT down-regulates C1a-CTR mRNA expression at least in part by a transcriptional mechanism, thereby contributing to the ligand-induced desensitization in cells of the osteoclast lineage [13].
• The proportion of CTR-positive cells expressing NSE and Mac-1 to total CTR-positive mononuclear cells decreased time dependently [20].
• The analog (CTR) and salmon calcitonin (sCT) stimulated kidney cell adenylate cyclase activity and inhibited bone resorption in organ cultures of fetal rat long bones with similar potencies and efficacies [2].

Other interactions of Calcr

• Greater than additive potentiations of CTR mRNA and RANKL mRNA and protein were observed when D3 and dexamethasone were combined [21].
• GM-CSF inhibited the development of mature function (bone resorption) to a greater extent than it inhibited CT-receptor-positive cell formation [22].
• Conversely, IL3, which also has no effect on mature osteoclasts, by itself induced CT-receptor expression but not bone resorption; in combination with 1,25(OH)2D3 it induced a threefold increase in bone resorption and CT-receptor-positive cells compared with cultures incubated with 1,25(OH)2D3 alone [22].
• Osteoclast-like cells expressed CT receptor (CTR), CT receptor-like receptor (CRLR) and RAMP2, but did not express RAMP1 or RAMP3 [23].
• These results indicated (1) that a pure population of osteoclast-like cells can be prepared by LCM and gene expression of this population can be analyzed by RT-PCR and (2) that RT-PCR shows that osteoclast-like cells express RAMP2, CTR and CRLR, suggesting the potential for adrenomedullin binding to osteoclast-like cells [23].

Analytical, diagnostic and therapeutic context of Calcr

• Cell culture assays suggest that amylin could affect bone formation and bone resorption, this latter function after its binding to the calcitonin receptor (CALCR) [1].
• RT-PCR amplification of messenger RNA indicated that the predominant isoform was the C1a CT receptor [16].
• All primary isolated osteoclasts from 1- to 3-day-old mouse long bones exhibited [125I]-sCT binding and TRAP activity and were strongly positive for CTR and TRAP mRNA by in situ hybridization [12].
• In the present study we investigated the mechanism of CTR messenger RNA (mRNA) down-regulation by CT in mouse cocultures of bone marrow and osteoblasts [13].
• CTR-bearing cells were detected by autoradiography of 125I-salmon CT binding, and cultures were stained for tartrate-resistant acid phosphatase (TRAP) [24].

References