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

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.

Murine IRF8 Mutation Offers New Insight into Osteoclast and Root Resorption

“…The FLNA gene encodes for actin-binding protein or filamin that crosslinks actin filaments into orthogonal networks in the cortical cytoplasm and plays a role in anchoring membrane proteins to the actin cytoskeleton (Stossel et al 2001; Razinia et al 2012). FLNA is required for monocyte migration during osteoclastogenesis via its role in regulating Rho GTPase-mediated actin remodeling (Leung et al 2010; Goldberg et al 2015). FLNA also interacts with low-density lipoprotein receptor-related protein 6 (LRP6) to inhibit β-catenin expression and enhances NFATc1-dependent osteoclastogenic gene expression to inhibit osteogenesis and promote osteoclastogenesis (Yang et al 2022).…”

Mouse Homolog of Human IRF8G388SMutation Provides Novel Insight into Osteoclastogenesis and Tooth Root Resorption

“…The FLNA gene encodes for actin-binding protein or filamin that crosslinks actin filaments into orthogonal networks in the cortical cytoplasm and plays a role in anchoring membrane proteins to the actin cytoskeleton (56,57) . FLNA is required for monocyte migration during osteoclastogenesis via its role in regulating Rho GTPase-mediated actin remodeling (58,59) .…”

Prognostic analysis and validation of diagnostic marker genes in patients with osteoporosis

“…( 53 ) showed that FLNA accumulates in the osteoblasts, and the osteoclasts were observed in the human OP samples. A report suggests that negative regulation of FLNA in mice is age-related and postmenopausal osteoporosis in vitro osteogenic differentiation in OP promotes RANKL-induced osteoclast differentiation ( 54 ). Zhang X et al.…”