Mice lacking the integrin beta5 subunit have accelerated osteoclast maturation and increased activity in the estrogen-deficient state.
ABSTRACT Integrin alphavbeta5 is expressed on osteoclast precursors and is capable of recognizing the same amino acid motif as alphavbeta3. Three-month-old beta5(-/-) female OVX mice had increased osteoclastogenesis ex vivo, and microCT assessment of trabecular bone volume was 53% lower than WT-OVX animals. These preliminary data suggest alphavbeta5 integrin's presence on osteoclast precursors may inhibit of osteoclast formation.
Osteoclasts are unique resorptive skeletal cells, capable of degrading bone on contact to the juxtaposed matrix. Integrin alphavbeta5 is expressed on osteoclast precursors, structurally similar to alphavbeta3, and capable of recognizing the same amino acid motif. Given the structural relationship and reciprocal regulation of alphavbeta3 and alphavbeta5, the purpose of this study was to evaluate how alphavbeta5 might contribute to osteoclast maturation and activity.
Three-month-old wildtype (WT) and beta5(-/-) female mice had ovariectomy (OVX) or sham operations. The osteoclastogenic capacity of marrow-derived precursors, the kinetic, the circulating, and structural parameters of bone remodeling, was determined after 6 weeks of paired feeding.
OVX increased osteoclastogenesis ex vivo and in vivo. Osteoclast formation and prolonged pre-osteoclast survival were substantially enhanced in cultures containing beta5(-/-) cells whether obtained from sham-operated or OVX mice. Expression of cathepsin K, beta3 integrin subunit, and calcitonin receptor were accelerated in cultured beta5(-/-)osteoclasts. beta5(-/-) osteoclasts from OVX animals showed a 3-fold enhancement of net resorptive activity, with quantitative muCT showing trabecular bone volume loss after OVX 53% greater in beta5(-/-) OVX compared with similarly treated WT OVX mice (p < 0.05). alpha5beta3 seems to be an inhibitor of osteoclast formation, in contrast to alphavbeta3. In addition, loss of alphavbeta5 seems to accelerate osteoclast formation in the OVX model. Further examination of alphavbeta5 signaling pathways may enhance our understanding of the activation of bone resorption.
Article: High-fat diet decreases cancellous bone mass but has no effect on cortical bone mass in the tibia in mice.[show abstract] [hide abstract]
ABSTRACT: Body mass has a positive effect on bone health. Whether mass derived from an obesity condition or excessive fat accumulation is beneficial to bone has not been established; neither have the mechanisms by which obesity affects bone metabolism. The aim of this study was to examine the effects of obesity on bone structure and osteoblastic expression of key markers involved in bone formation and resorption in a diet-induced obesity mouse model. Six-wk-old male C57BL/6 mice (n=21) were assigned to two groups and fed either a control (10 kcal% energy as fat) or high-fat diet (HFD, 45 kcal% energy as fat) for 14 weeks. Bone marrow stromal/osteoblastic cells (BMSC) were cultured. Osteoprogenitor activity [alkaline phosphatase (ALP) positive colonies] and mineralization (calcium nodule formation) were determined. Gene expression was measured using quantitative real-time PCR. Bone structure of proximal and midshaft tibia was evaluated by micro-computed tomography. Mice fed the HFD were 31% heavier (P<0.01) than those fed the control diet. There were more ALP positive colony forming units at d 14 and calcium nodules at d 28 of culture by BMSC from HFD mice than from control mice (P<0.01). Receptor activator of NF-kappaB ligand (RANKL) mRNA levels and the ratio of RANKL to osteoprotegerin expression in HFD animals was higher (P<0.01) than in control diet animals. Serum tartrate-resistant acid phosphatase levels were higher in HFD fed mice when compared to control diet fed mice (P<0.05). There were no significant differences in tibial fat-free weight, length, and cortical parameters of midshaft between the two groups. Compared with control mice, tibial trabecular bone volume was reduced, and trabecular separation was increased in HFD mice. Trabecular number was lower (P<0.05) and connectivity density tended to be less (P=0.07) in HFD mice than in control mice. In conclusion, our data indicate that obesity induced by a high-fat diet decreases cancellous bone mass but has no effect on cortical bone mass in the tibia in mice.Bone 03/2009; 44(6):1097-104. · 4.02 Impact Factor
Article: Inhibition of the progesterone nuclear receptor during the bone linear growth phase increases peak bone mass in female mice.[show abstract] [hide abstract]
ABSTRACT: Augmentation of the peak bone mass (PBM) may be one of the most effective interventions to reduce the risk of developing osteoporosis later in life; however treatments to augment PBM are currently limited. Our study evaluated whether a greater PBM could be achieved either in the progesterone nuclear receptor knockout mice (PRKO) or by using a nuclear progesterone receptor (nPR) antagonist, RU486 in mice. Compared to their wild type (WT) littermates the female PRKO mice developed significantly higher cancellous and cortical mass in the distal femurs, and this was associated with increased bone formation. The high bone mass phenotype was partially reproduced by administering RU486 in female WT mice from 1-3 months of age. Our results suggest that the inhibition of the nPR during the rapid bone growth period (1-3 months) increases osteogenesis, which results in acquisition of higher bone mass. Our findings suggest a crucial role for progesterone signaling in bone acquisition and inhibition of the nPR as a novel approach to augment bone mass, which may have the potential to reduce the burden of osteoporosis.PLoS ONE 01/2010; 5(7):e11410. · 4.09 Impact Factor
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ABSTRACT: The ARF tumor suppressor regulates p53 as well as basic developmental processes independent of p53, including osteoclast activation, by controlling ribosomal biogenesis. Here we provide evidence that ARF is a master regulator of bone remodeling and osteosarcoma (OS) development in mice. Arf(-/-) mice displayed increased osteoblast (OB) and osteoclast (OC) activity with a significant net increase in trabecular bone volume. The long bones of Arf(-/-) mice had increased expression of OB genes while Arf(-/-) OB showed enhanced differentiation in vitro. Mice transgenic for the Tax oncogene develop lymphocytic tumors with associated osteolytic lesions, while Tax+Arf(-/-) mice uniformly developed spontaneous OS by 7 months of age. Tax+Arf(-/-) tumors were well differentiated OS characterized by an abundance of new bone with OC recruitment, expressed OB markers and displayed intact levels of p53 mRNA and reduced Rb transcript levels. Cell lines established from OS recapitulated characteristics of the primary tumor, including the expression of mature OB markers and ability to form mineralized tumors when transplanted. Loss of heterozygosity in OS tumors arising in Tax+Arf(+/-) mice emphasized the necessity of ARF-loss in OS development. Hypothesizing that inhibition of ARF-regulated bone remodeling would repress development of OS, we demonstrated that treatment of Tax+Arf(-/-) mice with zoledronic acid, a bisphosphonate inhibitor of OC activity and repressor of bone turnover, prevented or delayed the onset of OS. These data describe a novel role for ARF as a regulator of bone remodeling through effects on both OB and OC. Finally, these data underscore the potential of targeting bone remodeling as adjuvant therapy or in patients with genetic predispositions to prevent the development of OS.PLoS ONE 01/2010; 5(12):e15755. · 4.09 Impact Factor