Evidence for a Hyperexcitability State of Staggerer Mutant Mice Macrophages

Kopmels, B.; Mariani, Jean; Delhaye‐Bouchaud, Nicole; Audibert, F.; Fradelizi, D; Wollman, Emmanuelle E.

doi:10.1111/j.1471-4159.1992.tb09295.x

Cited by 79 publications

(62 citation statements)

References 43 publications

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“…However, the tibia was not significantly shortened although the homozygote negative animals were of reduced size (40). The difference in tibial bone geometry may be related to the staggering gait, mild tremor, and hypotonia of the homozygotes (41). These factors are likely to influence muscle mass and strength and thus could indirectly also affect bone geometry.…”

Section: Discussionmentioning

confidence: 97%

In vitro and in vivo evidence for orphan nuclear receptor RORα function in bone metabolism

Meyer

Kneissel

Mariani

et al. 2000

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

105

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Bone is a major target site for steroid hormone action. Steroid hormones like cortisol, vitamin D, and estradiol are responsible for principal events associated with bone formation and resorption. Over the past decade, new members of the nuclear hormone gene family have been identified that lack known ligands. These orphan receptors can be used to uncover signaling molecules that regulate yet unidentified physiological networks. In the present study the function of retinoic acid receptor-related orphan receptor (ROR) ␣ in bone metabolism has been examined. We showed that ROR␣ and ROR␥, but not ROR␤, are expressed in mesenchymal stem cells derived from bone marrow. Interestingly, for ROR␣ we observed an increased messenger signal expression between control cells and cells undergoing osteogenic differentiation. Furthermore, the direct activation of mouse bone sialoprotein by ROR␣, typically 7-fold, has been shown. In contrast, transient overexpression of ROR␣ overrides the activation of the osteocalcin promoter by 1␣,25-dihydroxyvitamin D3. In addition, we have investigated bone mass parameters and bone geometry in the mouse mutant staggerer (sg͞sg), a mouse strain that carries a deletion within the ROR␣ gene. Homozygote mutants have thin long bones compared with the heterozygote animals and wild-type littermates. More interestingly, the bones of the sg͞sg animals are osteopenic as indicated by the comparison of bone mineral contents of sg͞sg animals to the heterozygote and wild-type animals. We conclude that these in vitro and in vivo results suggest a function for ROR␣ in bone biology. ROR␣ most likely acts by direct modulation of a bone matrix component. Bone is a metabolically highly active and organized tissue. The formation of bone by osteoblasts, and its remodeling by the bone multicellular unit, is a closely integrated homeostatic system. The osteoblast secretes the organic matrix, which is later mineralized. The bone extracellular matrix is composed mainly of layered type I collagen fibrils, other noncollagenous proteins such as the bone sialoprotein (BSP), a modulator of mineralization, osteopontin, which has been implicated in adhesion, and the bone-specific osteocalcin (OC), which plays an important role in bone formation (1).Mesenchymal stem cells (MSCs) are considered to be multipotent cells that are present in the adult marrow, can replicate as undifferentiated cells, and have the potential to differentiate into lineages of mesenchymal tissues, including bone, cartilage, fat, tendon, muscle, and marrow stroma. Recently it has been demonstrated that individual adult stem cells could indeed be induced to differentiate into adipocytic, chondrocytic, or osteocytic lineages (2). Even though the molecular basis for directing human MSCs toward the different lineages has been extensively studied, the interrelationship between each of the lineages and the control mechanism governing the differentiation of each of the lineages remains poorly understood. A key regulatory transcription factor in adipogenic diff...

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Section: Discussionmentioning

confidence: 97%

In vitro and in vivo evidence for orphan nuclear receptor RORα function in bone metabolism

Meyer

Kneissel

Mariani

et al. 2000

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

105

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“…Interestingly, stimulation of peripheral macrophage s of Rora sg/sg mutants by lipopolysaccharide (LPS) induces an abnormally high amount of pro-inflammatory cytokines IL-1, IL-6 and TNFα (40). In addition, Rora sg/sg mice are more susceptible to LPS-induced airway inflammation in the lung (41), and RORα has been reported to inhibit inflammatory responses in vascular smooth muscle cells (42).…”

Section: Proliferative and Neuroprotective Function Of Rorα In Thmentioning

confidence: 99%

Rorα, a pivotal nuclear receptor for Purkinje neuron survival and differentiation: From development to ageing

et al. 2006

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Abstract:RORα (Retinoid-related Orphan Receptor) is a transcription factor belonging to the superfamily of nuclear receptors. The spontaneous staggerer (sg) mutation, which consists of a deletion in the Rora ge ne, has been shown to cause the loss of function of the RORα protein. The total loss of RORα expression leads to cerebellar developmental defects, particularly to a dramatic decreased survival of Purkinje cells and an early block in the differentiation process. This review focuses on recent studies which position RORα as a pivotal factor controlling Purkinje cell survival and differentiation, from development to ageing.

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“…Homozygous sg/sg mutants have a delayed thymic development and a defect in terminating T-cell responses. 75 Moreover, peripheral macrophages of sg/sg mutants produce an abnormally high amount of proinflammatory cytokines IL-1, IL-6, and TNF␣ on LPS stimulation, 76 demonstrating a general condition of macrophage hyperexcitability. Interestingly, abnormal IL-1␤ cytokine production has been also described in the brain after peripheral LPS treatment.…”

Section: Inflammationmentioning

confidence: 99%

The “CholesteROR” Protective Pathway in the Vascular System

Boukhtouche

Mariani

Tedgui

2004

ATVB

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Abstract-Retinoic acid receptor-related Orphan Receptor ␣ (ROR␣) is a member of the nuclear hormone receptor superfamily. ROR␣ has long been considered as a constitutive activator of transcription in the absence of exogenous ligand; however, cholesterol has recently been identified as a natural ligand of ROR␣. The spontaneous staggerer (sg/sg) mutation is a deletion in the Rora gene that prevents the translation of the ligand-binding domain (LBD), leading to the loss of ROR␣ activity. The homozygous Rora sg/sg mutant mouse, of which the most obvious phenotype is ataxia associated with cerebellar degeneration, also displays a variety of other phenotypes, including several vascular ones; in particular, dysfunction of smooth muscle cells and enhanced susceptibility to atherosclerosis. Moreover, ROR␣ appears to participate in the regulation of plasma cholesterol levels, and has been shown to positively regulate apolipoprotein (apo)A-I and apoC-III gene expression. Yet its activity is regulated by cholesterol itself, making ROR␣ an intracellular cholesterol target. Key Words: ROR␣ Ⅲ cholesterol Ⅲ statins Ⅲ atherosclerosis Ⅲ lipid homeostasis R etinoic acid receptor-related Orphan Receptor ␣ (ROR␣), initially described as an orphan nuclear receptor, has recently been deorphanized by the identification of its natural ligand as cholesterol or a cholesterol derivative. 1,2 ROR␣ has been shown to be implicated in the development and/or differentiation of many tissues, and provides protection against age-related degenerative processes, including atherosclerosis. In addition, ROR␣ activates the apolipoprotein A-I (apoA-I) and apoC-III gene transcription, 3,4 modulates the vasomotor tone of small resistance arteries, and participates in the regulation of postischemic angiogenesis. 5,6 This review focuses on the link between ROR␣, vascular biology, and cholesterol homeostasis. Interestingly, recent findings suggest that ROR␣ is an intracellular cholesterol target. 1

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Evidence for a Hyperexcitability State of Staggerer Mutant Mice Macrophages

Cited by 79 publications

References 43 publications

In vitro and in vivo evidence for orphan nuclear receptor RORα function in bone metabolism

In vitro and in vivo evidence for orphan nuclear receptor RORα function in bone metabolism

Rorα, a pivotal nuclear receptor for Purkinje neuron survival and differentiation: From development to ageing

The “CholesteROR” Protective Pathway in the Vascular System

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