title: Adenylyl cyclase 6 mediates loading-induced bone adaptation in vivo.
abstract: Primary cilia are single, nonmotile, antenna-like structures extending from the apical membrane of most mammalian cells. They may mediate mechanotransduction, the conversion of external mechanical stimuli into biochemical intracellular signals. Previously we demonstrated that adenylyl cyclase 6 (AC6), a membrane-bound enzyme enriched in primary cilia of MLO-Y4 osteocyte-like cells, may play a role in a primary cilium-dependent mechanism of osteocyte mechanotransduction in vitro. In this study, we determined whether AC6 deletion impairs loading-induced bone formation in vivo. Skeletally mature mice with a global knockout of AC6 exhibited normal bone morphology and responded to osteogenic chemical stimuli similar to wild-type mice. Following ulnar loading over 3 consecutive days, bone formation parameters were assessed using dynamic histomorphometry. Mice lacking AC6 formed significantly less bone than control animals (41% lower bone formation rate). Furthermore, there was an attenuated flow-induced increase in COX-2 mRNA expression levels in primary bone cells isolated from AC6 knockout mice compared to controls (1.3±0.1- vs. 2.6±0.2-fold increase). Collectively, these data indicate that AC6 plays a role in loading-induced bone adaptation, and these findings are consistent with our previous studies implicating primary cilia and AC6 in a novel mechanism of osteocyte mechanotransduction.
authors.affiliation: 1Columbia University, 351 Engineering Terr., 1210 Amsterdam Ave., Mail Code 8904, New York, NY 10027, USA. crj2111@columbia.edu.
authors.forename: Kristen L
authors.initials: KL
authors.lastname: Lee
authors.forename: David A
authors.initials: DA
authors.lastname: Hoey
authors.forename: Milos
authors.initials: M
authors.lastname: Spasic
authors.forename: Tong
authors.initials: T
authors.lastname: Tang
authors.forename: H Kirk
authors.initials: HK
authors.lastname: Hammond
authors.forename: Christopher R
authors.initials: CR
authors.lastname: Jacobs
mesh_terms: D000222:Adaptation, Physiological; D000262:Adenylyl Cyclases / Q000378:metabolism*; D000818:Animals; D001842:Bone and Bones / Q000502:physiology*; D051546:Cyclooxygenase 2 / Q000235:genetics; D005260:Female; D008297:Male; D040542:Mechanotransduction, Cellular; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D012333:RNA, Messenger; D051546:Cyclooxygenase 2; D000262:Adenylyl Cyclases; C121100:adenylyl cyclase 6
keywords: fluid flow; mechanical loading; mechanotransduction