The Role of Connexin43 Gap Junction Protein in the Musculoskeletal Changes Induced by Mechanical Unloading
Open Access
- Author:
- Lloyd, Shane
- Graduate Program:
- Cell and Molecular Biology
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- May 09, 2013
- Committee Members:
- Henry Joseph Donahue, Dissertation Advisor/Co-Advisor
Henry Joseph Donahue, Committee Chair/Co-Chair
Charles H Lang, Committee Member
Neil Sharkey, Committee Member
James Robert Connor, Committee Member
Alicia Ellen Bateman, Special Member - Keywords:
- connexin43
unloading
bone loss
sclerostin
osteocyte
apoptosis
RANKL
muscle
spaceflight
atrophy
osteopenia - Abstract:
- Connexin43 (Cx43) is the predominant gap junction protein in bone. In the present study we examined the role of Cx43 in the skeletal response to mechanical unloading (i.e., lack of weight bearing). Mechanical unloading induces significant bone loss and muscle atrophy. A better understanding of the mechanisms underlying these deleterious effects is required in order to identify novel targets for therapeutic countermeasures. First, we collected tissue from mice following 0, 7, 14, and 21 days of hindlimb suspension (HLS) or normal loading. We found that muscle atrophy (due to decreased protein synthesis and increased protein degradation) precedes bone loss during mechanical unloading. Reduced mechanical force due to muscle atrophy may compound bone loss associated with a lack of weight bearing. Furthermore, age-related trabecular bone loss in mice, similar to that which occurs in mature astronauts, is superimposed on unloading. Preservation of muscle mass, cortical bone structure, and overall bone strength with age in normally loaded control mice suggests that muscle has a greater effect on cortical versus trabecular bone. Next, we sought to determine the role of Cx43 in unloading-induced bone loss by subjecting mice with a bone-specific deletion of Cx43 (cKO) to HLS. Following three weeks of HLS, wild-type (WT) mice experienced substantial bone loss; however, these deleterious effects were attenuated in cKO mice. Unloading also suppressed bone formation in WT mice, while there was no change from baseline for cKO-Suspended. mRNA levels of the gene encoding sclerostin, an osteocyte-derived inhibitor of bone formation, were greater in WT-Suspended, whereas cKO-Suspended was unchanged. The proportion of sclerostin-positive osteocytes was significantly lower in cKO-Control versus WT-Control, a difference accounted for by the presence of numerous empty lacunae and apoptotic osteocytes. There was no change in trabecular osteocyte viability. Osteoclast indices were lower in Suspended cKO versus WT-Suspended. Osteocyte apoptosis induced by Cx43 deficiency appears to preserve bone structure by preventing both suppression of bone formation and increased bone resorption during mechanical unloading. Attenuated trabecular bone loss, despite an apparent lack of affect on osteocyte viability in this compartment, suggests that an additional mechanism, independent of osteocyte apoptosis, may also be important.