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Deletion of Filamin A in Monocytes Protects Cortical and Trabecular Bone from Post-menopausal Changes in Bone Microarchitecture

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Abstract

The objective of the study was to determine the in vivo role of Filamin A (FLNA) in osteoclast generation and function, through the assessment of trabecular bone morphology, bone turnover, and the resulting changes in mechanical properties of the skeleton in mice with targeted deletion of FLNA in pre-osteoclasts. Using a conditional targeted knockdown of FLNA in osteoclasts, we assessed bone characteristics in vivo including micro-computed tomography (micro-ct), histomorphometric analyses, and bone mechanical properties. These parameters were assessed in female mice at 5 months of age, in an aging protocol (comparing 5-month-old and 11-month-old mice) and an osteoporosis protocol [ovariectomized (OVX) at 5 months of age and then sacrificed at 6 and 11 months of age]. In vivo bone densitometry, mechanical and histomorphometric analyses revealed a mild osteoporotic phenotype in the FLNA-null 5-month and aging groups. The WT and FLNA-KO bones did not appear to age differently. However, the volumetric bone mineral density decrease associated with OVX in WT is absent in FLNA-KO-OVX groups. The skeleton in the FLNA-KO-OVX group does not differ from the FLNA-KO group both in mechanical and structural properties as shown by mechanical testing of femora and vertebrae and histomorphometry of vertebrae. Additionally, FLNA-KO femora are tougher and more ductile than WT femora. The result of this study indicates that while FLNA-KO bones are weaker than WT bones, they do not age differently and are protected from estrogen-mediated post-menopausal osteoporosis.

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Acknowledgments

The work was supported by a CIHR operating grant to Dr. Michael Glogauer. Stephanie Goldberg participated in making substantial contributions to conception and design, acquisition of data and analysis, and interpretation of data. Stephanie Goldberg, Marc Grynpas, and Michael Glogauer participated in drafting the manuscript and revising it critically for important intellectual content. Marc Grynpas and Michael Glogauer approved the final version of the submitted manuscript, and all three authors agreed to be accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work were appropriately investigated and resolved. Judah Glogauer participated in data acquisition.

Conflict of interest

Stephanie Goldberg, Judah Glogauer, Marc Grynpas, and Michael Glogauer have no conflicts of interest to disclose.

Human and Animal Rights and Informed Consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000 (5). Informed consent was obtained from all patients for being included in the study.

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Authors and Affiliations

  1. Matrix Dynamics Group- Faculty of Dentistry, Fitzgerald Building 150 College Street, Toronto, ON, M5S3E2, Canada

    S. Goldberg, J. Glogauer & M. Glogauer

  2. Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, 600 University Ave, Toronto, ON, M5G1X5, Canada

    S. Goldberg & M. D. Grynpas

Authors
  1. S. Goldberg
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  2. J. Glogauer
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  3. M. D. Grynpas
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  4. M. Glogauer
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Correspondence to S. Goldberg.

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Goldberg, S., Glogauer, J., Grynpas, M.D. et al. Deletion of Filamin A in Monocytes Protects Cortical and Trabecular Bone from Post-menopausal Changes in Bone Microarchitecture. Calcif Tissue Int 97, 113–124 (2015). https://doi.org/10.1007/s00223-015-9994-4

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  • DOI: https://doi.org/10.1007/s00223-015-9994-4

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