Abstract
BackgroundGrowth of endochondral bones is regulated through the activity of cartilaginous growth plates. Disruption of the physiological patterns of chondrocyte proliferation and differentiation – such as in endocrine disorders or in many different genetic diseases (e.g. chondrodysplasias) – generally results in dwarfism and skeletal defects. For example, glucocorticoid administration in children inhibits endochondral bone growth, but the molecular targets of these hormones in chondrocytes remain largely unknown. In contrast, recent studies have shown that C-type Natriuretic Peptide (CNP) is an important anabolic regulator of cartilage growth, and loss-of-function mutations in the human CNP receptor gene cause dwarfism. We asked whether glucocorticoids could exert their activities by interfering with the expression of CNP or its downstream signaling components.MethodsPrimary mouse chondrocytes in monolayer where incubated with the synthetic glucocorticoid Dexamethasone (DEX) for 12 to 72 hours. Cell numbers were determined by counting, and real-time PCR was performed to examine regulation of genes in the CNP signaling pathway by DEX.ResultsWe show that DEX does influence expression of key genes in the CNP pathway. Most importantly, DEX significantly increases RNA expression of the gene encoding CNP itself (Nppc). In addition, DEX stimulates expression of Prkg2 (encoding cGMP-dependent protein kinase II) and Npr3 (natriuretic peptide decoy receptor) genes. Conversely, DEX was found to down-regulate the expression of the gene encoding its receptor, Nr3c1 (glucocorticoid receptor), as well as the Npr2 gene (encoding the CNP receptor).ConclusionOur data suggest that the growth-suppressive activities of DEX are not due to blockade of CNP signaling. This study reveals a novel, unanticipated relationship between glucocorticoid and CNP signaling and provides the first evidence that CNP expression in chondrocytes is regulated by endocrine factors.
Highlights
Growth of endochondral bones is regulated through the activity of cartilaginous growth plates
We first examined whether DEX would affect the cell number of primary mouse chondrocytes in monolayer culture
Primary chondrocytes were incubated with DMSO or 10-7 M DEX for 12 to 72 hours, and Nr3c1 mRNA levels were determined by real-time polymerase chain reaction (PCR) relative to Gapdh
Summary
Growth of endochondral bones is regulated through the activity of cartilaginous growth plates. BMC Musculoskeletal Disorders 2006, 7:87 http://www.biomedcentral.com/1471-2474/7/87 regulated by the activity of the Sox transcription factor, which controls the expression of principal genes encoding the extracellular matrix proteins of cartilage, such as collagen type II and aggrecan [4]. Another transcription factor, Runx, promotes hypertrophic differentiation and stimulates expression of type X collagen, a marker of hypertrophic chondrocytes [5]. Recent studies have demonstrated an intricate weave of signaling pathways regulating endochondral ossification, including many hormones and growth factors, such as glucocorticoids and C-type natriuretic peptide (CNP) [6,7,8,9]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
