title: Dexamethasone stimulates expression of C-type Natriuretic Peptide in chondrocytes.
abstract: BACKGROUND
  Growth 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.
  
  
  METHODS
  Primary 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.
  
  
  RESULTS
  We 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).
  
  
  CONCLUSIONS
  Our 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.
authors.affiliation: CIHR Group in Skeletal Development and Remodeling, Department of Physiology and Pharmacology, University of Western Ontario, London, ON, Canada. hagosto@uwo.ca <hagosto@uwo.ca>
authors.forename: Hanga
authors.initials: H
authors.lastname: Agoston
authors.forename: Laurie
authors.initials: L
authors.lastname: Baybayan
authors.forename: Frank
authors.initials: F
authors.lastname: Beier
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D019902:Chondrocytes / Q000187:drug effects* / Q000378:metabolism*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000235:genetics; D003907:Dexamethasone / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D005938:Glucocorticoids / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000235:genetics; D051379:Mice; D020098:Natriuretic Peptide, C-Type / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D017461:Receptors, Atrial Natriuretic Factor / Q000235:genetics; D011965:Receptors, Glucocorticoid / Q000235:genetics; D013997:Time Factors; D015854:Up-Regulation; D000099242:Atrial Natriuretic Factor Receptor B
chemical_list: D017869:Cyclic GMP-Dependent Protein Kinases; D003907:Dexamethasone; D005938:Glucocorticoids; D006162:Guanylate Cyclase; D020098:Natriuretic Peptide, C-Type; D012333:RNA, Messenger; D017461:Receptors, Atrial Natriuretic Factor; D011965:Receptors, Glucocorticoid; D000099242:Atrial Natriuretic Factor Receptor B; C073616:atrial natriuretic factor receptor C