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Updated: Jun 10, 2026
A Novel in vivo Gene Transfer Technique and in vitro Cell Based Assays for the Study of Bone Loss in Musculoskeletal Disorders
Published on: June 8, 2014
Novel actions of bisphosphonates in bone: preservation of osteoblast and osteocyte viability
Teresita Bellido1, Lilian I Plotkin
1Department of Anatomy and Cell Biology, Indiana University School of Medicine, Indianapolis, USA. tbellido@iupui.edu
Abstract:
Bisphosphonates stop bone loss by inhibiting the activity of bone-resorbing osteoclasts. However, the effect of bisphosphonates on bone mass cannot completely explain the reduction in fracture incidence observed in patients treated with these agents. Recent research efforts provided an explanation to this dichotomy by demonstrating that part of the beneficial effect of bisphosphonates on the skeleton is due to prevention of osteoblast and osteocyte apoptosis. Work of our group, independently confirmed by other investigators, demonstrated that bisphosphonates are able to prevent osteoblast and osteocyte apoptosis in vitro and in vivo. This prosurvival effect is strictly dependent on the expression of connexin (Cx) 43, as demonstrated in vitro using cells lacking Cx43 or expressing dominant-negative mutants of the protein as well as in vivo using Cx43 osteoblast/osteocyte-specific conditional knock-out mice. Remarkably, this Cx43-dependent survival effect of bisphosphonates is independent of gap junctions and results from opening of Cx43 hemichannels. Hemichannel opening leads to activation of the kinases Src and extracellular signal-regulated kinases (ERKs), followed by phosphorylation of the ERK cytoplasmic target p90(RSK) kinase and its substrates BAD and C/EBPβ, resulting in inhibition of apoptosis. The antiapoptotic effect of bisphosphonates is separate from the effect of the drugs on osteoclasts, as analogs that lack antiresorptive activity are still able to inhibit osteoblast and osteocyte apoptosis in vitro. Furthermore, a bisphosphonate analog that does not inhibit osteoclast activity prevented osteoblast and osteocyte apoptosis and the loss of bone mass and strength induced by glucocorticoids in mice. Preservation of the bone-forming function of mature osteoblasts and maintenance of the osteocytic network, in combination with lack anticatabolic actions, open new therapeutic possibilities for bisphosphonates in the treatment of osteopenic conditions in which decreased bone resorption is not desired.
Insights
Bisphosphonates prevent osteoblast and osteocyte apoptosis via connexin 43 hemichannel opening, independent of their bone resorption inhibition. This offers new therapeutic avenues for bone loss conditions.
Area of Science:
- Bone Biology
- Cell Signaling
- Pharmacology
Background:
- Bisphosphonates reduce fracture risk, but their effect on bone mass doesn't fully explain this benefit.
- Osteoclast inhibition by bisphosphonates is the primary mechanism, yet other effects are suspected.
- Recent research suggests bisphosphonates may protect bone cells from programmed cell death (apoptosis).
Purpose of the Study:
- To investigate the mechanism by which bisphosphonates prevent osteoblast and osteocyte apoptosis.
- To determine the role of connexin 43 (Cx43) in the anti-apoptotic effects of bisphosphonates.
- To explore the therapeutic potential of bisphosphonates independent of their antiresorptive activity.
Main Methods:
- In vitro studies using cells with manipulated Cx43 expression.
- In vivo studies utilizing Cx43-deficient mice.
- Analysis of signaling pathways including Src, ERKs, p90(RSK), BAD, and C/EBPβ.
- Testing of bisphosphonate analogs with and without antiresorptive activity.
Main Results:
- Bisphosphonates prevent osteoblast and osteocyte apoptosis in vitro and in vivo.
- This prosurvival effect is dependent on connexin 43 (Cx43) expression.
- The mechanism involves Cx43 hemichannel opening, leading to Src and ERK activation and downstream anti-apoptotic signaling.
- Bisphosphonate analogs lacking antiresorptive activity retain the ability to inhibit apoptosis.
Conclusions:
- Bisphosphonates exert a prosurvival effect on osteoblasts and osteocytes through a Cx43 hemichannel-dependent pathway.
- This anti-apoptotic action is distinct from their effect on osteoclasts.
- Bisphosphonates offer potential therapeutic applications for osteopenic conditions beyond simply reducing bone resorption.
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