Disruption of Four-and-a-Half LIM 2 Decreases Bone Mineral Content and Bone Mineral Density in Femur and Tibia Bones of Female Mice

Abstract

Four-and-a-half LIM 2 (FHL2) is a member of a family of LIM domain proteins which mediate protein-protein interactions. FHL2 acts as a coactivator and binds to important regulators of bone formation such as insulin-like growth factor binding protein (IGFBP)-5, androgen receptor, and beta-catenin. We hypothesized that FHL2 is an important regulator of bone formation. We evaluated growth and skeletal parameters in FHL2 knockout (KO) and wild-type (WT) mice at 4, 8, and 12 weeks of age. At 4 weeks of age, lack of FHL2 reduced femur, tibia, and total bone mineral content (BMC) and body weight in all mice. A gender-by-treatment interaction (P <or= 0.05) was observed for several parameters due to a greater reduction in females. Specifically, femur BMC was reduced 11-27% at 8 and 12 weeks of age and BMD was reduced 7-13% at all ages in female KO mice (P < 0.05). A similar reduction was observed in the tibias at 8 weeks of age. A 6% reduction (P = 0.07) in femur cortical thickness was observed at 12 weeks of age in female KO mice. Interestingly, a gender-specific reduction in IGFBP-5 expression was observed in the femurs of female KO mice. During differentiation of bone marrow stromal cells into osteoblasts, expression of osteocalcin, alkaline phosphatase, and bone sialoprotein was reduced 47-96% in FHL2 KO cells (P < 0.001). In conclusion, FHL2 is an important regulator of peak bone mass, lack of FHL2 produces gender- and site-specific effects on bone accretion and IGFBP-5 expression, and FHL2 is important for optimal osteoblast differentiation in vitro.

Rac1 Inhibition Via Srgap2 Restrains Inflammatory Osteoclastogenesis and Limits the Clastokine, SLIT3

“…However, at 8 weeks of age, we observed the increased trabecular bone phenotype only in female in Srgap2‐cKO mice. Sex‐restricted phenotypes in genetic mouse models are not uncommon . Skeletal sexual dimorphism depends not only on androgen action in males and estrogen action in females, but also on complex sex‐specific and time‐specific interactions between sex hormones, the growth hormone/insulin‐like growth factor‐1 (GH/IGF‐1) axis, and mechanical loading.…”

Female mice lacking p47phoxhave altered adipose tissue gene expression and are protected against high fat-induced obesity

“…9). In addition, other pro-osteoblastic genes, Ihh (Indian hedgehog) (10) and four-and-a half LIM 2 (Fhl2) (9,16), were elevated in the P47KO HFD group compared with the WT:HFD group. Gja1 (gap junction protein alpha 1, connexin 36), another regulator of osteoblast development (3,22), was also elevated in the P47KO HFD group (Fig.…”

FHL2 mediates dexamethasone‐induced mesenchymal cell differentiation into osteoblasts by activating Wnt/β‐catenin signaling‐dependent Runx2 expression

“…In contrast, FHL2 potentiates the ␤-catenin transactivating function of Wntresponsive genes in endothelial cells (37). Recent data indicate that FHL2 deficiency results in osteopenia in mice, whereas FHL2 transgenic mice exhibit increased bone mass, suggesting its implication in the control of osteoblast activity (38,39). Consistently, FHL2 was found to interact with integrins to promote osteoblast differentiation (40).…”