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Critical role of beta3 integrin in experimental postmenopausal osteoporosis
Haibo Zhao1, Hideki Kitaura, Mark S Sands
1Department of Pathology and Immunology, Washington University School of Medicine, St Louis, Missouri, USA.
Unlabelled:
We show that mice lacking beta3 integrin are protected from OVX-induced bone loss. Using a lentiviral-based strategy to express beta3 mutants in beta3(-/-) mice, we also show that beta3(S752), but not beta3(Y747/Y759), is important for osteoclastic bone resorption in vivo.
Introduction:
Mice lacking the beta3 integrin have dysfunctional osteoclasts and therefore accumulate bone mass with age. Thus, the alphavbeta3 integrin is a potential anti-osteoporosis target. Identifying components of the beta3 integrin that determine its function in vivo is essential for therapeutically exploiting the antiresorptive properties of alphavbeta3.
Materials And Methods:
We used DXA and histomorphometry to assess bone loss after ovariectomy in wildtype and beta3 integrin null mice. We used lentiviral vectors carrying various human beta3 (hbeta3) integrin constructs to transduce beta3(-/-) bone marrow and reconstituted lethally irradiated beta3(-/-) mice with the transduced marrow. The expressed constructs include the intact integrin and two mutants, namely hbeta3(Y747F/Y759F) and hbeta3(S752P), each of which induces the bleeding dyscrasia, Glanzmann's thrombasthenia, in humans. Two months after transplantation, the expression of hbeta3 was measured by flow cytometry of marrow-derived macrophages. Osteoclast differentiation and function were assessed ex vivo by TRACP and actin-ring staining, respectively. Reconstituted mice were ovariectomized, and bone loss was assessed by DXA, histomorphometry, and serum TRACP5b assay.
Results:
beta3(-/-) mice are protected from ovariectomy-induced bone loss, showing no difference in BMD compared with sham-operated controls. We successfully expressed hbeta3 integrins in beta3(-/-) hosts using lentiviral transduction of bone marrow. Two months after transplantation, 25-35% of marrow-derived macrophages expressed the hbeta3 constructs. Similar to its effect in vitro, hbeta3(WT) completely rescued the osteoclast and platelet phenotype of beta3(-/-) mice. Whereas platelet function remained deranged in beta3(-/-) mice overexpressing hbeta3(Y747F/Y759F), osteoclast function was fully restored. In contrast, beta3(-/-) mice expressing hbeta3(S752P) continued to exhibit prolonged bleeding times and dysfunctional osteoclasts in vitro and ex vivo. Most importantly, hbeta3(WT) and hbeta3(Y747F/Y759F) transplanted mice underwent equivalent ovariectomy-induced bone loss, whereas, like those bearing the control vector, hbeta3(S752P) transplanted mice were protected.
Conclusions:
Functional beta3 integrin is required for ovariectomy-induced bone loss. beta3(S752), but not beta3(Y747/Y759), is critical for osteoclast function in vivo.
Insights
Mice lacking beta3 integrin are protected from osteoporosis. Specific beta3 integrin components, like beta3(S752), are crucial for osteoclast function and bone resorption in vivo.
Area of Science:
- Integrin signaling in bone biology.
- Osteoclast differentiation and function.
- Integrin alphaVbeta3 in bone homeostasis.
Background:
- Beta3 integrin deficiency leads to dysfunctional osteoclasts and increased bone mass.
- AlphaVbeta3 integrin is a potential therapeutic target for osteoporosis.
- Understanding beta3 integrin's in vivo function is key for developing anti-resorptive therapies.
Purpose of the Study:
- To investigate the role of beta3 integrin in ovariectomy-induced bone loss.
- To identify specific beta3 integrin components critical for osteoclast function in vivo.
- To evaluate the therapeutic potential of targeting beta3 integrin for osteoporosis.
Main Methods:
- Ovariectomy in wildtype and beta3 integrin null mice.
- Lentiviral transduction of beta3(-/-) bone marrow with human beta3 integrin constructs (WT, Y747F/Y759F, S752P).
- Assessment of bone loss using DXA, histomorphometry, and serum TRACP5b assays; evaluation of osteoclast function ex vivo.
Main Results:
- Beta3 integrin null mice were protected from ovariectomy-induced bone loss.
- Expression of wildtype and Y747F/Y759F beta3 integrin rescued osteoclast function, while S752P mutant did not.
- Mice expressing wildtype and Y747F/Y759F beta3 integrin experienced bone loss post-ovariectomy, unlike those with S752P mutant or control vector.
Conclusions:
- Functional beta3 integrin is essential for ovariectomy-induced bone loss.
- The serine residue at position 752 (beta3(S752)) is critical for osteoclast function in vivo.
- The tyrosine residues at positions 747 and 759 (beta3(Y747/Y759)) are not essential for osteoclast-mediated bone resorption in vivo.
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