Bone homeostasis in growth hormone receptor–null mice is restored by IGF-I but independent of Stat5

Sims, Natalie A.; Clément-Lacroix, Philippe; Ponte, Francesca Da; Bouali, Yasmina; Binart, Nadine; Moriggl, Richard; Goffin, Vincent; Coschigano, Karen T.; Gaillard-Kelly, Martine; Kopchick, John J.; Baron, Roland; Kelly, Paul A.

doi:10.1172/jci10753

Cited by 232 publications

(183 citation statements)

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“…Whether p53 and STAT5 are implicated in this OSM-induced differentiation of osteoblasts deserves further investigations but recent in vivo studies with p53 knockout mice indicated that p53 inhibits osteoblast differentiation, bone development and neoplasia (Lengner et al, 2006;Wang et al, 2006). Similarly, STAT5ab À/À mice, although smaller than their wild-type littermates, have an increased number of trabecular osteoblasts and bone formation (Sims et al, 2000).…”

Section: Discussionmentioning

confidence: 99%

Sensitization of osteosarcoma cells to apoptosis by oncostatin M depends on STAT5 and p53

et al. 2007

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Oncostatin M (OSM), a cytokine of the interleukin-6 family, induces growth arrest and differentiation of osteoblastic cells into glial-like/osteocytic cells. Here, we asked whether OSM regulates apoptosis of normal or transformed (osteosarcoma) osteoblasts. We show that OSM sensitizes cells to apoptosis induced by various death inducers such as staurosporine, ultraviolet or tumor necrosis factor-a. Apoptosis is mediated by the mitochondrial pathway, with release of cytochrome c from the mitochondria to the cytosol and activation of caspases-9 and -3. DNA micro-arrays revealed that OSM modulates the expression of Bax, Bad, Bnip3, Bcl-2 and Mcl-1. Pharmacological inhibitors, dominant-negative signal transducer and activator of transcriptions (STATs), stable RNA interference and knockout cells indicated that the transcription factors p53 and STAT5, which are activated by OSM, are implicated in the sensitization to apoptosis, being responsible for Bax induction and Bcl-2 reduction, respectively. These results indicate that, in addition to growth arrest and induced differentiation, OSM also sensitizes normal and transformed osteoblasts to apoptosis by a mechanism implicating (i) activation and nuclear translocation of STAT5 and p53 and (ii) an increased Bax/Bcl-2 ratio. Therefore, association of OSM with kinase inhibitors such as Sts represents new therapeutic opportunities for wild-type p53 osteosarcoma.

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Section: Discussionmentioning

confidence: 99%

Sensitization of osteosarcoma cells to apoptosis by oncostatin M depends on STAT5 and p53

et al. 2007

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“…MicroCT scans, quantitative computerized tomography and histomorphometry of mouse tibia were performed as described (21,22) (for details see Supporting Text).…”

Section: Lithium and Parathyroid Hormone (Pth) Treatment Regimens Andmentioning

confidence: 99%

Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice

Clément-Lacroix

Morvan

et al. 2005

Proc. Natl. Acad. Sci. U.S.A.

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459

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One of the well characterized cell biologic actions of lithium is the inhibition of glycogen synthase kinase-3␤ and the consequent activation of canonical Wnt signaling. Because deficient Wnt signaling has been implicated in disorders of reduced bone mass, we tested whether lithium could improve bone mass in mice. We gavage-fed lithium chloride to 8-week-old mice from three different strains (Lrp5 ؊/؊ , SAMP6, and C57BL͞6) and assessed the effect on bone metabolism after 4 weeks of therapy. Lrp5 ؊/؊ mice lack the Wnt coreceptor low-density lipoprotein receptor-related protein 5 and have markedly reduced bone mass. Lithium, which is predicted to act downstream of this receptor, restored bone metabolism and bone mass to near wild-type levels in these mice. SAMP6 mice have accelerated osteoporosis due to inadequate osteoblast renewal. Lithium significantly improved bone mass in these mice and in wild-type C57BL͞6 mice. We found that lithium activated canonical Wnt signaling in cultured calvarial osteoblasts from Lrp5 ؊/؊ mice ex vivo and that lithium-treated mice had increased expression of Wnt-responsive genes in their bone marrow cells in vivo. These data lead us to conclude that lithium enhances bone formation and improves bone mass in mice and that it may do so via activation of the canonical Wnt pathway. Lithium has been used safely and effectively for over half a century in the treatment of bipolar illness. Prospective studies in patients receiving lithium should determine whether it also improves bone mass in humans.anabolic ͉ osteoporosis ͉ therapy

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“…Body weight of GHR/ BP j/j mice, with measurements starting just after birth, did not differ significantly from normal (+/+) littermates until 2-3 weeks of age (Zhou et al 1997;Lupu et al 2001). Rate of growth in the following weeks was significantly slower for the GHR/BP j/j mice (Zhou et al 1997;Coschigano et al 2000 and2003;Lupu et al 2001;Sims et al 2000). Maximal adult weight of the GHR/BP j/j mice averaged õ40% the weight of the +/+ mice and was reached at an earlier age than the +/+ mice (Coschigano et al , 2003.…”

Section: Small Body Size and Reduced Skeletal Growthmentioning

confidence: 85%

“…While most organ weights were proportionately decreased in the GHR/BP j/j mice as compared to the +/+ mice, at some of the examined ages liver and kidney were found to be disproportionately smaller and brain disproportionately larger in the GHR/BP j/j mice (Coschigano et al 2003;Lupu et al 2001;Ng et al 1999;Sjö gren et al 2000;Berryman et al 2004). Body length of the GHR/BP j/j mice was also significantly less than that of the +/+ mice, although the body length difference was not as dramatic as the body weight difference (Zhou et al 1997;Lupu et al 2001;Sims et al 2000;Sjö gren et al 2000). GHR/BP j/j mice exhibited disproportional skeletal growth, decreased bone mineral content and reduced bone turnover (Lupu et al 2001;Sims et al 2000;Sjö gren et al 2000).…”

Section: Small Body Size and Reduced Skeletal Growthmentioning

confidence: 90%

“…Body length of the GHR/BP j/j mice was also significantly less than that of the +/+ mice, although the body length difference was not as dramatic as the body weight difference (Zhou et al 1997;Lupu et al 2001;Sims et al 2000;Sjö gren et al 2000). GHR/BP j/j mice exhibited disproportional skeletal growth, decreased bone mineral content and reduced bone turnover (Lupu et al 2001;Sims et al 2000;Sjö gren et al 2000). Lupu et al suggested that their observations could be indicative of developmental delays due to hypoproliferation in combination with a reduced size of hypertrophic chondrocytes.…”

Section: Small Body Size and Reduced Skeletal Growthmentioning

confidence: 99%

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Aging-related characteristics of growth hormone receptor/binding protein gene-disrupted mice

Coschigano

2006

AGE

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Since generation of the growth hormone receptor/binding protein (GHR/BP) gene-disrupted mouse nearly 10 years ago, use of this mouse model has become widespread in the elucidation of the physiological roles of GH and insulin-like growth factor-1 (IGF-1). In particular, it serves as a useful model to study mechanisms of aging. This review highlights the evidence demonstrating that the loss of GH signaling leads to lifespan extension in mice, and presents the multiple characteristics of this mouse line that suggest the life extension is due to alteration of the aging process.

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Bone homeostasis in growth hormone receptor–null mice is restored by IGF-I but independent of Stat5

Cited by 232 publications

References 50 publications

Sensitization of osteosarcoma cells to apoptosis by oncostatin M depends on STAT5 and p53

Sensitization of osteosarcoma cells to apoptosis by oncostatin M depends on STAT5 and p53

Lrp5-independent activation of Wnt signaling by lithium chloride increases bone formation and bone mass in mice

Aging-related characteristics of growth hormone receptor/binding protein gene-disrupted mice

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