Caveolin-1 Knockout Mice Have Increased Bone Size and Stiffness

Abstract

The skeletal phenotype of the cav-1 −/− mouse, which lacks caveolae, was examined. µCT and histology showed increased trabecular and cortical bone caused by the gene deletion. Structural changes were accompanied by increased mechanical properties. Cell studies showed that cav-1 deficiency leads to increased osteoblast differentiation. These results suggest that cav-1 helps to maintain osteoblast progenitors in a less differentiated state. Introduction:The absence of caveolin-1 in cellular membranes causes dysregulated signaling. To understand the role of the caveolar microdomain in bone homeostasis, we examined the skeletal phenotype of 5-and 8-wk-old cav-1 −/− mice. Materials and Methods: High-resolution CT imaging showed a region-specific effect of cav-1 deficiency on the skeleton. At 5 wk, cav-1 −/− mice had increased epiphyseal bone volume (+58.4%, p ‫ס‬ 0.05); at 8 wk, metaphyseal bone volume was increased by 77.4% (p ‫ס‬ 0.008). Cortical bone at the femoral mid-diaphysis showed that the periosteal area of cav-1 −/− mice significantly exceeded that of cav-1 +/+ mice by 23.9% and 16.3% at 5 and 8 wk, respectively, resulting in increased mechanical properties (I max : +38.2%, p ‫ס‬ 0.003 and I mi : +23.7%, p ‫ס‬ 0.03). Results: Histomorphometry complemented CT results showing increased bone formation rate (BFR) at trabecular and cortical sites at 5 wk, which supported findings of increased bone at 8 wk in cav-1 −/− mice. Formal mechanical testing of the femoral diaphysis confirmed increased bone structure: stiffness increased 33% and postyield deflection decreased 33%. Stromal cells from cav-1 −/− marrow showed a 23% increase in von Kossa-positive nodules; osteoclastogenesis was also modestly increased in cav-1-deficient marrow. Knockdown of cav-1 with siRNA in wildtype stromal cells increased alkaline phosphatase protein and expression of osterix and Runx2, consistent with osteoblast differentiation. Conclusions: These data suggest that cav-1 helps to maintain a less differentiated state of osteoblast progenitor cells, and the absence of cav-1 causes bone to mature more rapidly. Caveolin-1 may thus be a target for altering skeletal homeostasis.

Caveolin-1 Regulates Osteoclastogenesis and Bone Metabolism in a Sex-dependent Manner

“…Some of our results are in agreement and disagreement with the data shown in some previous studies in which the effects of Cav-1 deficiency on bone were investigated (39,40). In the paper by Rubin et al (39), distal femur metaphysis of 8-weekold Cav-1 Ϫ/Ϫ male mice showed increased trabecular BV/TV with an apparently paradoxical decrease in MAR compared with WT mice.…”

Cellular Factor XIIIA Transglutaminase Localizes in Caveolae and Regulates Caveolin-1 Phosphorylation, Homo-oligomerization and c-Src Signaling in Osteoblasts

“…The role of caveolae and Cav-1 in the negative regulation of bone formation is based on solid animal studies (Rubin et al 2007). Skeletal phenotyping of Cav-1-knockout mice has shown increased trabecular number and thickness.…”

Lipid Rafts as Master Regulators of Breast Cancer Cell Function

“…Caveolins -1 and -2 are abundantly expressed in most cell types, including adipocytes, fibroblasts, endothelial and epithelial cells (Fan et al, 1983;Galbiati et al, 2001). Caveolin-3 expression however is restricted to muscle (Rubin et al, 2007). The N-terminal region of caveolin-1 contains a scaffolding domain which aids interactions with various signalling molecules, illustrating the potential importance of caveolin-1 for the signalling functions of caveolar lipid rafts (Everson & Smart, 2006).…”