TY - JOUR
T1 - Urocortin is a novel regulator of osteoclast differentiation and function through inhibition of a canonical transient receptor potential 1-like cation channel
AU - Combs, Charlotte E.
AU - Fuller, Karen
AU - Kumar, Hashethra
AU - Albert, Anthony P.
AU - Pirianov, Grisha
AU - McCormick, James
AU - Locke, Ian C.
AU - Chambers, Timothy J.
AU - Lawrence, Kevin M.
PY - 2012/2
Y1 - 2012/2
N2 - This study investigated the role of urocortin (UCN), a member of the corticotrophin-releasing factor (CRF) family of peptides, in osteoclast maturation and function. We found that 10 -7 M UCN significantly (P < 0·05) suppressed osteoclast differentiation from bone marrow precursor cells in culture and reduced the expression of several osteoclastic markers. Furthermore, UCN potently suppressed osteoclast bone resorption, by significantly inhibiting both the plan area of bone resorbed by osteoclasts and actin ring formation within osteoclasts at 10 -9M (P < 0·05), with complete inhibition at 10 -7M (P < 0·001). UCN also inhibited osteoclast motility (10 -7 M) but had no effect on osteoclast survival. Osteoclasts expressed mRNA encoding both UCN and the CRF receptor 2β subtype. Pre-osteoclasts however, expressed CRF receptor 2β alone. Unstimulated osteoclasts contained constitutively active cation channel currents with a unitary conductance of 3-4 pS, which were inhibited by over 70% with UCN (10 -7 M). Compounds that regulate calcium signalling and energy status of the cell, both crucial for osteoclast activity were investigated. The non-selective cation channel blockers, lanthanum (La 3+) and gadolinium (Gd 3+), inhibited actin ring formation in osteoclasts, whereas modulators of voltage-dependent Ca 2+ channels and K ATP channels had no effect. These findings show for the first time that UCN is a novel anti-resorptive molecule that acts through a direct effect on osteoclasts and their precursor cells.
AB - This study investigated the role of urocortin (UCN), a member of the corticotrophin-releasing factor (CRF) family of peptides, in osteoclast maturation and function. We found that 10 -7 M UCN significantly (P < 0·05) suppressed osteoclast differentiation from bone marrow precursor cells in culture and reduced the expression of several osteoclastic markers. Furthermore, UCN potently suppressed osteoclast bone resorption, by significantly inhibiting both the plan area of bone resorbed by osteoclasts and actin ring formation within osteoclasts at 10 -9M (P < 0·05), with complete inhibition at 10 -7M (P < 0·001). UCN also inhibited osteoclast motility (10 -7 M) but had no effect on osteoclast survival. Osteoclasts expressed mRNA encoding both UCN and the CRF receptor 2β subtype. Pre-osteoclasts however, expressed CRF receptor 2β alone. Unstimulated osteoclasts contained constitutively active cation channel currents with a unitary conductance of 3-4 pS, which were inhibited by over 70% with UCN (10 -7 M). Compounds that regulate calcium signalling and energy status of the cell, both crucial for osteoclast activity were investigated. The non-selective cation channel blockers, lanthanum (La 3+) and gadolinium (Gd 3+), inhibited actin ring formation in osteoclasts, whereas modulators of voltage-dependent Ca 2+ channels and K ATP channels had no effect. These findings show for the first time that UCN is a novel anti-resorptive molecule that acts through a direct effect on osteoclasts and their precursor cells.
UR - http://www.scopus.com/inward/record.url?scp=84856793429&partnerID=8YFLogxK
U2 - 10.1530/JOE-11-0254
DO - 10.1530/JOE-11-0254
M3 - Article
C2 - 22083217
AN - SCOPUS:84856793429
SN - 0022-0795
VL - 212
SP - 187
EP - 197
JO - Journal of Endocrinology
JF - Journal of Endocrinology
IS - 2
ER -