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The calcitonin gene family of peptides: receptor expression and effects on bone cells
Umeå University, Faculty of Medicine, Odontology.
2008 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

The calcitonin gene family of peptides consists of calcitonin (CT), two calcitonin gene related peptides (α-CGRP, β-CGRP), adrenomedullin (ADM), amylin (AMY), three calcitonin receptor activating peptides (CRSP1-3) and intermedin/adrenomedullin2 (IMD). These peptides bind to one of two G protein -coupled receptors, the calcitonin receptor (CTR) or the calcitonin receptor-like receptor (CRLR). The receptor specificity to different ligands is dependent on the formation of a complex with one of three receptor activity-modifying proteins (RAMP1-3).

The aim of this study was to analyse effects of this family of peptides on the formation of osteoclasts and bone resorption, and the expression of the receptor components in bone cells.

CT inhibited the formation of multinucleated osteoclasts in spleen cell cultures and in bone marrow macrophage cultures (BMM) without affecting a number of genes important for osteoclast differentiation, activity or fusion of osteoclast progenitor cells. All members of the CT family, except ADM, inhibited osteoclastogenesis in BMM. The inhibitory effect seemed to involve activation of both protein kinase A and the exchange protein directly activated by cyclic AMP (Epac) signalling. BMM expressed the CRLR, RAMP1-3 and the receptor component protein (RCP). AMY, ADM, CGRP and IMD, but not CRSP and CT, increased cyclic AMP (cAMP) levels in these cells, indicating the presence of functional receptors. Stimulation of BMM with RANKL gradually increased the levels of CTR mRNA as well as the capacity of the cells to respond to the stimulation by CRSP and CT. The response to stimulation of ADM was, on the contrary, decreased by RANKL. Stimulation of RANKL caused a transiently enhanced CRLR mRNA expression and transiently decreased RAMP1, but did not affect RAMP2, RAMP3, or RCP mRNA. However, RANKL did not affect protein levels of CRLR or RAMP1-3. CT, CGRP, AMY, ADM, IMD and CRSP all down regulated the CTR mRNA, but none of the peptides caused any effects on the expression of CRLR or any of the RAMPs.

All members of the CT family, except ADM, rapidly and transiently, inhibited bone resorption in mouse calvarial bones. CT, CGRP, AMY and CRSP also significantly stimulated cAMP formation in the calvaria. cAMP analogues specifically stimulating the PKA or the Epac pathways did not cause inhibition of bone resorption in the calvaria. An unspecific cAMP analogue, stimulating both pathways did, however, cause inhibition.

Analyses of an osteoblastic cell line, MC3T3-E1, showed that these cells express the mRNA for CRLR and all three RAMP proteins.

In conclusion, the results of this thesis show that all peptides in CT family of peptides, except ADM, inhibit of bone resorption and osteoclast formation and that these effects involve the adenylate cyclase-cAMP pathway. Furthermore, expressions of CRLR and RAMP1-3 mRNA have been demonstrated on osteoclasts, as well as in an osteoblastic cell line.

Place, publisher, year, edition, pages
Umeå: Odontologi , 2008. , 77 p.
Series
Umeå University odontological dissertations, ISSN 0345-7532 ; 102
Keyword [en]
CT family of peptides, osteoclast differentiation, bone resorption, CTR, CRLR, RAMPs
National Category
Cell Biology
Identifiers
URN: urn:nbn:se:umu:diva-1571ISBN: 978-91-7264-498-4 (print)OAI: oai:DiVA.org:umu-1571DiVA: diva2:141409
Public defence
2008-03-27, Sal D, 9tr, Umeå, 09:00 (English)
Opponent
Supervisors
Available from: 2008-03-07 Created: 2008-03-07 Last updated: 2009-04-22Bibliographically approved
List of papers
1. Calcitonin inhibits osteoclast formation in mouse hematopoetic cells independently of transcriptional regulation by RANK and c-Fms
Open this publication in new window or tab >>Calcitonin inhibits osteoclast formation in mouse hematopoetic cells independently of transcriptional regulation by RANK and c-Fms
2007 (English)In: Journal of endocrinology, ISSN 0022–0795/07/0195–415, Vol. 195, no 3, 415-427 p.Article in journal (Refereed) Published
Identifiers
urn:nbn:se:umu:diva-2991 (URN)
Available from: 2008-03-07 Created: 2008-03-07Bibliographically approved
2. Expression of the calcitonin receptor, calcitonin receptor-like receptor, and receptor activity modifying proteins during osteoclast differentiation.
Open this publication in new window or tab >>Expression of the calcitonin receptor, calcitonin receptor-like receptor, and receptor activity modifying proteins during osteoclast differentiation.
2008 (English)In: Journal of cellular biochemistry, ISSN 1097-4644, Vol. 104, no 3, 920-933 p.Article in journal (Refereed) Published
Abstract [en]

The expressions of the calcitonin receptor (CTR), the calcitonin receptor-like receptor (CLR), the receptor activity-modifying proteins (RAMP) 1-3, and of the receptor component protein (RCP) have been studied in mouse bone marrow macrophages (BMM) during osteoclast differentiation, induced by treatment with M-CSF and RANKL. Analyses of mRNA showed that CLR and RAMP1-3, but not CTR, were expressed in M-CSF stimulated BMM. RANKL gradually increased CTR mRNA, transiently enhanced CLR and transiently decreased RAMP1 mRNA, but did not affect RAMP2, RAMP3, or RCP mRNA. However, RANKL did not affect protein levels of CLR or RAMP1-3 as assessed by Western blots or FACS analyses, whereas immunocytochemistry showed enhanced CTR protein. Analyses of cAMP production showed that BMM cells expressed functional receptors for calcitonin gene-related peptide (CGRP), amylin, adrenomedullin, and intermedin, but not for calcitonin and calcitonin receptor stimulating peptide (CRSP), but that RANKL induced the expression of receptors for calcitonin and CRSP as well. Calcitonin, CGRP, amylin, adrenomedullin, intermedin, and CRSP all down regulated the CTR mRNA, but none of the peptides caused any effects on the expression of CLR or any of the RAMPs. Our data show that BMM cells express receptors for CGRP, amylin, adrenomedullin, and intermedin and that RANKL induces the formation of receptors for calcitonin and CRSP in these cells. We also show, for the first time, that the CTR is not only down regulated by signaling through the CTR but also by the peptides signaling through CLR/RAMPs.

Identifiers
urn:nbn:se:umu:diva-20444 (URN)10.1002/jcb.21674 (DOI)18384073 (PubMedID)
Available from: 2009-03-19 Created: 2009-03-19 Last updated: 2009-12-02
3. Calcitonin receptor-stimulating peptide and intermedin inhibit bone resorption, osteoclast activity and osteoclastogenesis
Open this publication in new window or tab >>Calcitonin receptor-stimulating peptide and intermedin inhibit bone resorption, osteoclast activity and osteoclastogenesis
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-2993 (URN)
Available from: 2008-03-07 Created: 2008-03-07 Last updated: 2010-01-13Bibliographically approved
4. Expression of the calcitonin receptor, calcitonin receptor-like receptor and receptor activity modifying proteins in primary osteoblast-like cells
Open this publication in new window or tab >>Expression of the calcitonin receptor, calcitonin receptor-like receptor and receptor activity modifying proteins in primary osteoblast-like cells
Manuscript (Other academic)
Identifiers
urn:nbn:se:umu:diva-2994 (URN)
Available from: 2008-03-07 Created: 2008-03-07 Last updated: 2010-01-13Bibliographically approved

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