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Regulating DeltaFosB expression in adult Tet-Off-DeltaFosB transgenic mice alters bone formation and bone mass
N A Sims1, G Sabatakos, J-S Chen
1Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06520-8044, USA.
Abstract:
The DeltaFosB isoforms are naturally occurring AP-1 family members that increase bone volume via a cell-autonomous effect on osteoblastic bone formation. Mice overexpressing DeltaFosB demonstrate a very high level of bone formation, resulting in a progressive osteosclerosis. Despite the linkage of bone formation and resorption in physiological systems, no alteration in bone resorption was detected in mice overexpressing DeltaFosB. To determine whether altering DeltaFosB expression can regulate bone formation independently of bone resorption in adult mice, we used the Tet-Off-inducible transgene system to induce or block transgenic DeltaFosB overexpression and thereby regulate bone formation in vivo. Overexpression of DeltaFosB after skeletal maturity increased trabecular bone volume by increasing bone formation, again without altering bone resorption, indicating that developmental DeltaFosB overexpression is not required for the osteosclerotic phenotype. Similarly, switching off DeltaFosB overexpression after osteosclerosis had developed led to a marked decrease in bone formation and loss of bone mass such that trabecular bone volume approached normal levels. Despite this dramatic reduction, no alteration in bone resorption was detected. These results clearly demonstrate that DeltaFosB regulates bone formation and bone mass in adult mice with no effect on bone resorption.
Insights
DeltaFosB significantly increases bone volume by enhancing osteoblastic bone formation without affecting bone resorption. This protein regulates bone mass independently in adult mice.
Area of Science:
- Molecular Biology
- Bone Biology
- Genetics
Background:
- DeltaFosB, an AP-1 family member, is known to increase bone volume.
- Overexpression of DeltaFosB in mice leads to osteosclerosis, characterized by high bone formation.
- The relationship between bone formation and resorption is complex and tightly regulated.
Purpose of the Study:
- To investigate if DeltaFosB can regulate bone formation independently of bone resorption in adult mice.
- To determine the role of DeltaFosB in maintaining bone mass after skeletal maturity.
Main Methods:
- Utilized a Tet-Off-inducible transgene system in mice to control DeltaFosB expression.
- Induced and blocked DeltaFosB overexpression in adult mice to observe effects on bone.
- Quantified changes in bone volume, bone formation, and bone resorption.
Main Results:
- DeltaFosB overexpression post-skeletal maturity increased trabecular bone volume by enhancing bone formation, without altering bone resorption.
- Reversing DeltaFosB overexpression led to decreased bone formation and bone mass, approaching normal levels, with no change in resorption.
- These findings demonstrate a dissociation between DeltaFosB's regulation of bone formation and resorption.
Conclusions:
- DeltaFosB is a key regulator of bone formation and bone mass in adult mice.
- DeltaFosB's effects on bone mass are independent of its influence on bone resorption.
- Targeting DeltaFosB may offer therapeutic strategies for bone mass regulation.