Premium
Connexin 43 Is Required for the Anti‐Apoptotic Effect of Bisphosphonates on Osteocytes and Osteoblasts In Vivo
Author(s) -
Plotkin Lilian I,
Lezcano Virginia,
Thostenson Jeff,
Weinstein Robert S,
Manolagas Stavros C,
Bellido Teresita
Publication year - 2008
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1359/jbmr.080617
Subject(s) - connexin , in vivo , apoptosis , osteocyte , osteoblast , chemistry , cancer research , microbiology and biotechnology , medicine , pharmacology , in vitro , gap junction , biology , biochemistry , genetics , intracellular
Connexin (Cx)43 is required for inhibition of osteocyte and osteoblast apoptosis by bisphosphonates in vitro. Herein, we evaluated its requirement for the in vivo actions of bisphosphonates using mice in which Cx43 was deleted specifically from osteocytes and osteoblasts (Cx43 ΔOb−Ot/− mice). Effective removal of Cx43 was confirmed by the presence of the deleted form of the gene and by reduced mRNA and protein expression in osteoblastic cells and bones obtained from Cx43 ΔOb−Ot/− mice. The amino‐bisphosphonate alendronate (2.3 μmol/kg/d) was injected daily into 5‐mo‐old female mice ( n = 6–11) for 31 days, starting 3 days before implantation of pellets releasing the glucocorticoid prednisolone (2.1 mg/kg/d). Cx43 ΔOb−Ot/− mice and their littermates (Cx43 fl/− , Cx43 ΔOb−Ot/+ , and Cx43 fl/+ ) gained bone with similar kinetics and exhibited identical bone mass from 2 to 4.5 mo of age, indicating that Cx43 deletion from osteocytes and mature osteoblasts does not impair bone acquisition. In addition, prednisolone induced a similar increase in osteocyte and osteoblast apoptosis in Cx43 ΔOb−Ot/− or in control Cx43 fl/− littermates. However, whereas alendronate prevented prednisolone‐induced apoptosis in control Cx43 fl/− mice, it was ineffective in Cx43 ΔOb−Ot/− mice. In contrast, alendronate inhibited glucocorticoid‐induced bone loss in both type of animals, suggesting that inhibition of resorption is the predominant effect of alendronate against the early phase of glucocorticoid‐induced bone loss. Taken together with earlier in vitro evidence, these findings show that Cx43 is required for the anti‐apoptotic effect of bisphosphonates on osteocytes and osteoblasts.