ACTH promotes chondrogenic nodule formation and induces transient elevations in intracellular calcium in rat bone marrow cell cultures via MC2-R signaling.
Adrenocorticotropic hormone (ACTH) is among several melanocortin peptide hormones that are derived from proopiomelanocortin (POMC). ACTH has been found to enhance osteogenesis and chondrogenesis. We show that, in the presence of dexamethasone, ACTH dose-dependently increases chondrogenic nodule formation in bone marrow stromal cells (BMSC) from the Wistar Kyoto (WKY) rat. The nodules consist in condensed cells highly expressing alkaline phosphatase, Sox9 and type II collagen transcripts and a proteoglycan-rich matrix. Immunoblot analysis of crude membrane fractions has shown that these cells express three melanocortin receptors (MC-R), namely MC2-R, MC3-R and MC5-R and the melanocortin 2-receptor accessory protein (MRAP). To determine which of these receptors mediate ACTH-induced effects, we have used MC-R-specific peptides and the known agonist profiles of the receptors. Neither α-MSH, a strong agonist of MC5-R, nor γ2-MSH, a strong agonist of MC3-R, duplicates ACTH effects in rat BMSC. In addition, calcium flux has been examined as a mechanism for ACTH action at the MC2-R. Consistent with MC2-R and MRAP expression patterns in the BMSC cultures, ACTH-induced transient increases in intracellular calcium are increased with dexamethasone treatment. Neither α-MSH nor γ2-MSH affects calcium flux. Dexamethasone increases MC2-R and MRAP expression and POMC peptide expression and cleavage increasing the production of the lipolytic β-lipotropic hormone product. Therefore, the effects of ACTH in rat BMSC enriched for mesenchymal progenitors are consistent with an MC2-R signaling mechanism, with dexamethasone being capable of regulating components of the melanocortin system in these cells.
Vascular Biology, Winthrop University Hospital, Mineola, NY 11501, USA. jevans@winthrop.org
Jodi F
JF
Evans
Sylvana
S
Rodriguez
Louis
L
Ragolia
D000324:Adrenocorticotropic Hormone / Q000494:pharmacology*; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D020219:Chondrogenesis / Q000187:drug effects; D008565:Membrane Proteins / Q000096:biosynthesis; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D011333:Pro-Opiomelanocortin / Q000378:metabolism; D051381:Rats; D011921:Rats, Inbred WKY; D044103:Receptor, Melanocortin, Type 2 / Q000378:metabolism*
C560868:MRAP protein, mouse; D008565:Membrane Proteins; D044103:Receptor, Melanocortin, Type 2; D011333:Pro-Opiomelanocortin; D000324:Adrenocorticotropic Hormone; D002118:Calcium