Abstract
Young, skeletally mature mice lacking Cx43 in osteocytes exhibit increased osteocyte apoptosis and decreased bone strength, resembling the phenotype of old mice. Further, the expression of Cx43 in bone decreases with age, suggesting a contribution of reduced Cx43 levels to the age-related changes in the skeleton. We report herein that Cx43 overexpression in osteocytes achieved by using the DMP1-8kb promoter (Cx43OT mice) attenuates the skeletal cortical, but not trabecular bone phenotype of aged, 14-month-old mice. The percentage of Cx43-expressing osteocytes was higher in Cx43OT mice, whereas the percentage of Cx43 positive osteoblasts remained similar to wild type (WT) littermate control mice. The percentage of apoptotic osteocytes and osteoblasts was increased in aged WT mice compared to skeletally mature, 6-month-old WT mice, and the percentage of apoptotic osteocytes, but not osteoblasts, was decreased in age-matched Cx43OT mice. Aged WT mice exhibited decreased bone formation and increased bone resorption as quantified by histomorphometric analysis and circulating markers, compared to skeletally mature mice. Further, aged WT mice exhibited the expected decrease in bone biomechanical structural and material properties compared to young mice. Cx43 overexpression prevented the increase in osteoclasts and decrease in bone formation on the endocortical surfaces, and the changes in circulating markers in the aged mice. Moreover, the ability of bone to resist damage was preserved in aged Cx43OT mice both at the structural and material level. All together, these findings suggest that increased Cx43 expression in osteocytes ameliorates age-induced cortical bone changes by preserving osteocyte viability and maintaining bone formation, leading to improved bone strength.
Highlights
Advanced age is associated with skeletal fragility as a result of decreases in bone quantity and quality due to changes in the structural and material properties of bone.[1,2] Bone remodeling, a coordinated process critical for the maintenance of bone quality, occurs throughout life; the rate of bone turnover significantly decreases with advancing skeletal age.[3,4] Alterations in bone turnover where resorption outweighs formation eventually result in bone loss in old age
The critical role of Cx43 in early and mature osteoblasts as well as in osteocytes has been demonstrated in numerous studies.[13,14,15] We previously showed that removal of Cx43 from osteocytes results in a skeletal phenotype that resembles that of aged mice with increased osteocyte apoptosis, enhanced osteoclast recruitment to bone surfaces, and defective bone material properties.[13,16] Further, Cx43 is significantly decreased in old mice and humans.[4,16] Overall, these findings demonstrate the essential role that Cx43 plays in maintaining osteocyte viability and bone homeostasis, underscoring the potential contribution of reduced levels of Cx43 in osteocytes to the bone weakness in aging
To confirm that our DMP1-8kb-Cx43/ GFP transgene is primarily expressed in osteocytes and not in osteoblasts, Cx43OT mice were crossed with DMP1-8kb-GFP mice.[16,21] GFP-positive osteocytes (Ot) isolated by FACS expressed high levels of the osteocyte markers SOST, DMP1, and FGF23, whereas the osteoblast marker keratocan was low (Fig. 1A)
Summary
Advanced age is associated with skeletal fragility as a result of decreases in bone quantity and quality due to changes in the structural and material properties of bone.[1,2] Bone remodeling, a coordinated process critical for the maintenance of bone quality, occurs throughout life; the rate of bone turnover significantly decreases with advancing skeletal age.[3,4] Alterations in bone turnover where resorption outweighs formation eventually result in bone loss in old age. The critical role of Cx43 in early and mature osteoblasts as well as in osteocytes has been demonstrated in numerous studies.[13,14,15] We previously showed that removal of Cx43 from osteocytes results in a skeletal phenotype that resembles that of aged mice with increased osteocyte apoptosis, enhanced osteoclast recruitment to bone surfaces, and defective bone material properties.[13,16] Further, Cx43 is significantly decreased in old mice and humans.[4,16] Overall, these findings demonstrate the essential role that Cx43 plays in maintaining osteocyte viability and bone homeostasis, underscoring the potential contribution of reduced levels of Cx43 in osteocytes to the bone weakness in aging. Because overexpression of Cx43 in osteocytes does not significantly affect cancellous bone, these findings point to a site-specific effect of Cx43 in osteocytes
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