Caveolin-1 knockout mice have increased bone size and stiffness.
The skeletal phenotype of the cav-1(-/-) mouse, which lacks caveolae, was examined. muCT 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.


BACKGROUND
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.


METHODS
High-resolution microCT 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 (I(max): +38.2%, p = 0.003 and I(mi): +23.7%, p = 0.03).


RESULTS
Histomorphometry complemented microCT 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.
Rubin
Janet
J
Department of Medicine,University of North Carolina, Chapel Hill, North Carolina 27599, USA. janet_rubin@med.unc.edu
Schwartz
Zvi
Z
Boyan
Barbara D
BD
Fan
Xian
X
Case
Natasha
N
Sen
Buer
B
Drab
Marcus
M
Smith
Deborah
D
Aleman
Maria
M
Wong
Kevin L
KL
Yao
Hai
H
Jo
Hanjoong
H
Gross
Ted S
TS
D000818:Animals; D001696:Biomechanical Phenomena; D001842:Bone and Bones / Q000033:anatomy & histology* / Q000166:cytology; D051242:Caveolin 1 / Q000235:genetics / Q000502:physiology*; D020868:Gene Silencing; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010006:Osteoblasts / Q000166:cytology
D051242:Caveolin 1