Caveolin-1 knockout mice have increased bone size and stiffness

Janet Rubin, Zvi Schwartz, Barbara D. Boyan, Xian Fan, Natasha Case, Buer Sen, Marcus Drab, Deborah Smith, Maria Aleman, Kevin L. Wong, Hai Yao, Hanjoong Jo, Ted S. Gross

Research output: Contribution to journalArticle

56 Scopus citations

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 μCT 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 = 0.05); at 8 wk, metaphyseal bone volume was increased by 77.4% (p = 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 (Imax: +38.2%, p = 0.003 and Imi: +23.7%, p = 0.03). Results: Histomorphometry complemented μCT 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.

Original languageEnglish (US)
Pages (from-to)1408-1418
Number of pages11
JournalJournal of Bone and Mineral Research
Volume22
Issue number9
DOIs
StatePublished - Sep 2007

Keywords

  • Biomechanics
  • Histomorphometry
  • Osteoblast
  • siRNA
  • μCT

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

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