title: Connexin 43 deficiency desensitizes bone to the effects of mechanical unloading through modulation of both arms of bone remodeling.
abstract: Connexin 43 (Cx43) is a gap junction protein that plays an integral role in the skeletal response to mechanical loading and unloading. In a previous study, we demonstrated preservation of trabecular bone mass and cortical bone formation rate in mice with an osteoblast/osteocyte-selective deficiency of Cx43 (cKO) following mechanical unloading via hindlimb suspension (HLS). In the present study, we sought to define the potential mechanisms underlying this response. Following three weeks of HLS, mRNA levels of Sost were significantly greater in wild-type (WT)-Suspended mice vs. WT-Control, while there was no difference between cKO control and cKO-Suspended. Unloading-induced decreases in P1NP, a serum marker of bone formation, were also attenuated in cKO-Suspended. The proportion of sclerostin-positive osteocytes was significantly lower in cKO-Control vs. WT-Control (-72%, p<0.05), a difference accounted for by the presence of numerous empty lacunae in the cortical bone of cKO vs. WT. Abundant TUNEL staining was present throughout the cortical bone of the tibia and femur, suggesting an apoptotic process. There was no difference in empty lacunae in the trabecular bone of the tibia or femur. Trabecular and cortical osteoclast indices were lower in cKO-Suspended vs. WT-Suspended; however, mRNA levels of the gene encoding RANKL increased similarly in both genotypes. Connexin 43 deficient mice experience attenuated sclerostin-mediated suppression of cortical bone formation and lower cortical osteoclast activity during unloading. Preservation of trabecular bone mass and attenuated osteoclast activity during unloading, despite an apparent lack of effect on osteocyte viability at this site, suggests that an additional mechanism independent of osteocyte apoptosis may also be important. These findings indicate that Cx43 is able to modulate both arms of bone remodeling during unloading.
authors.affiliation: Division of Musculoskeletal Sciences, Department of Orthopaedics and Rehabilitation, Penn State College of Medicine, 500 University Drive, Hershey, PA 17033, USA.
authors.forename: Shane A
authors.initials: SA
authors.lastname: Lloyd
authors.forename: Alayna E
authors.initials: AE
authors.lastname: Loiselle
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.forename: Henry J
authors.initials: HJ
authors.lastname: Donahue
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D016723:Bone Remodeling / Q000502:physiology; D001842:Bone and Bones / Q000166:cytology* / Q000378:metabolism*; D018031:Connexin 43 / Q000235:genetics / Q000378:metabolism*; D006023:Glycoproteins / Q000378:metabolism; D020287:In Situ Nick-End Labeling; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism; D010011:Osteocytes / Q000166:cytology / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018031:Connexin 43; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D053245:RANK Ligand; C486030:Sost protein, mouse
keywords: Connexin 43; Osteocyte apoptosis; RANKL; Sclerostin; Unloading
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