Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL

Sobacchi, Cristina; Frattini, Annalisa; Guerrini, Matteo M.; Abinun, Mario; Pangrazio, Alessandra; Susani, Lucia; Bredius, Robbert G. M.; Mancini, Grazia M.S.; Cant, Andrew J.; Bishop, Nick; Grabowski, Peter; Fattore, Andrea Del; Messina, Chiara; Errigo, G; Coxon, Fraser P.; Scott, Derek Anthony; Teti, Anna; Rogers, Michael J.; Vezzoni, Paolo; Villa, Anna; Helfrich, Miep

doi:10.1038/ng2076

Cited by 349 publications

(250 citation statements)

References 15 publications

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“…The TNFSF11 gene is a member of the TNF superfamily localized at 13q14, with eight exons. Mutations in the gene lead to an osteoclast-poor form of osteopetrosis in humans (32). Promoter SNPs of the TNFSF11 gene are good candidates for the genetic regulation of BMD.…”

Section: Discussionmentioning

confidence: 99%

Allelic variations of RANKL/OPG signaling system are related to bone mineral density and in vivo gene expression

Takács

Lazáry

Kósa

et al. 2010

European Journal of Endocrinology

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Objective: Receptor activator of nuclear factor-kB ligand/osteoprotegerin (RANKL/OPG) signaling system plays a crucial role in the regulation of bone resorption. Polymorphic variations in the genes may have an influence on gene expression and bone metabolism. In the present study, we aimed to investigate the influence of RANKL/OPG allelic variations on the in vivo human gene expression of five genes, bone mineral density (BMD), and fracture incidence in Hungarian postmenopausal women. Methods: Three hundred and sixty postmenopausal women (61.6G7.9 years) were genotyped. All together, five single nucleotide polymorphisms (SNPs) in the two genes have been investigated. In addition, bone samples from 17 examined subjects were acquired for gene expression studies. Bone densities and fracture data have also been collected. Results: All two SNPs in OPG gene and three SNPs in RANKL gene showed correlation with BMD. Haplotype analysis of these genes gave similar results. The 'CCT' haplotype of RANKL promoter region, which was associated with decreased BMD, exhibited a significantly upregulated expression of RANKL mRNA, while the other haplotypes of RANKL or OPG 15 genes did not. No correlation between genetic variations and fracture data was found. Conclusion: We have demonstrated associations between RANKL and OPG haplotypes and BMD as well as between RANKL haplotypes and in vivo RANKL expression in a Hungarian postmenopausal population. Moreover, we have found a new RANKL haplotype associating with reduced BMD and increased in vivo RANKL expression in human bone tissue.

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Section: Discussionmentioning

confidence: 99%

Allelic variations of RANKL/OPG signaling system are related to bone mineral density and in vivo gene expression

Takács

Lazáry

Kósa

et al. 2010

European Journal of Endocrinology

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“…Human osteoclasts were generated from peripheral blood monocytes cultured with 20 ng/mL M-CSF (R&D Systems) and 100 ng/mL receptor activator of NF-kappaB ligand (RANKL) (Peprotech EC Ltd) as previously described (37). Samples of whole blood were obtained with informed consent from healthy volunteers with approval from the Local Research Ethics Committee.…”

Section: Methodsmentioning

confidence: 99%

The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo

Whyte

Ryberg

Sims

et al. 2009

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

293

328

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GPR55 is a G protein-coupled receptor recently shown to be activated by certain cannabinoids and by lysophosphatidylinositol (LPI). However, the physiological role of GPR55 remains unknown. Given the recent finding that the cannabinoid receptors CB 1 and CB2 affect bone metabolism, we examined the role of GPR55 in bone biology. GPR55 was expressed in human and mouse osteoclasts and osteoblasts; expression was higher in human osteoclasts than in macrophage progenitors. Although the GPR55 agonists O-1602 and LPI inhibited mouse osteoclast formation in vitro, these ligands stimulated mouse and human osteoclast polarization and resorption in vitro and caused activation of Rho and ERK1/2. These stimulatory effects on osteoclast function were attenuated in osteoclasts generated from GPR55 ؊/؊ macrophages and by the GPR55 antagonist cannabidiol (CBD). Furthermore, treatment of mice with this non-psychoactive constituent of cannabis significantly reduced bone resorption in vivo. Consistent with the ability of GPR55 to suppress osteoclast formation but stimulate osteoclast function, histomorphometric and microcomputed tomographic analysis of the long bones from male GPR55 ؊/؊ mice revealed increased numbers of morphologically inactive osteoclasts but a significant increase in the volume and thickness of trabecular bone and the presence of unresorbed cartilage. These data reveal a role of GPR55 in bone physiology by regulating osteoclast number and function. In addition, this study also brings to light an effect of both the endogenous ligand, LPI, on osteoclasts and of the cannabis constituent, CBD, on osteoclasts and bone turnover in vivo.A role for the endocannabinoid system (1) in the regulation of bone mass has been demonstrated recently, because mice lacking either of the cannabinoid receptors CB 1 or CB 2 have abnormal bone phenotypes. Furthermore, cannabinoid receptor agonists and inverse agonists reduce bone loss in mice following ovariectomy and have direct effects on both bone-resorbing cells (osteoclasts) and bone-forming cells (osteoblasts) in vitro (2, 3).In some systems such as the vasculature, there is considerable evidence for a role of non-CB 1 /non-CB 2 receptors in mediating some of the effects of certain cannabinoid ligands (for review, see ref. 4). Such non-CB 1 /non-CB 2 effects have been observed with a range of cannabinoid ligands including certain endocannabinoids and the phytocannabinoid-like compound O-1602; these effects are antagonized by the cannabis constituent cannabidiol (CBD) (4). Recently, the G protein-coupled receptor GPR55 has been shown to be activated by O-1602 (EC 50 ϭ 13 nM) and antagonized by CBD (IC 50 ϭ 445 nM) (5-8). In contrast, these compounds have low affinity (5-30 M) for CB 1 and CB 2 receptors (9, 10). GPR55 also is activated by the bioactive lipid, L-␣-lysophosphatidylinositol (LPI) (11,12).The physiological role(s) of GPR55 remains unknown. Given the apparent role of CB 1 and CB 2 in regulating bone mass, we examined whether GPR55 is expressed by osteoblasts and osteoc...

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“…This definition focuses on the resorptive side of bone remodeling, however, and recognizes direct (for example, ADO due to ClC-7 defects within the osteoclast) and indirect regulatory defects. Examples of the latter are defects in the receptor for RANKL at the resorptive, osteoclastic site (RANK) (78), and mutations in RANKL by itself on the osteoblastic site (210). This definition acknowledges regulatory (autocrine/ paracrine/endocrine) pathways within bone remodeling and also points to the fact that bone formation is ongoing in osteopetrosis.…”

Section: Updated Definition Of Clinical Osteopetrosismentioning

confidence: 99%

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Bollerslev

Henriksen

Nielsen

et al. 2013

European Journal of Endocrinology

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Systematic studies of autosomal dominant osteopetrosis (ADO) were followed by the identification of underlying mutations giving unique possibilities to perform translational studies. What was previously designated ADO1 turned out to be a high bone mass phenotype caused by a missense mutation in the first propeller of LRP5, a region of importance for binding inhibitory proteins. Thereby, ADO1 cannot be regarded as a classical form of osteopetrosis but must now be considered a disease of LRP5 activation. ADO (Albers-Schönberg disease, or previously ADO2) is characterized by increased number of osteoclasts and a defect in the chloride transport system (ClC-7) of importance for acidification of the resorption lacuna (a form of Chloride Channel 7 Deficiency Osteopetrosis). Ex vivo studies of osteoclasts from ADO have shown that cells do form normally but have reduced resorption capacity and an expanded life span. Bone formation seems normal despite decreased osteoclast function. Uncoupling of formation from resorption makes ADO of interest for new strategies for treatment of osteoporosis. Recent studies have integrated bone metabolism in whole-body energy homeostasis. Patients with ADO may have decreased insulin levels indicating importance beyond bone metabolism. There seems to be a paradigm shift in the treatment of osteoporosis. Targeting ClC-7 might introduce a new principle of dual action. Drugs affecting ClC-7 could be antiresorptive, still allowing ongoing bone formation. Inversely, drugs affecting the inhibitory site of LRP5 might stimulate bone formation and inhibit resorption. Thereby, these studies have highlighted several intriguing treatment possibilities, employing novel modes of action, which could provide benefits to the treatment of osteoporosis.

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Osteoclast-poor human osteopetrosis due to mutations in the gene encoding RANKL

Cited by 349 publications

References 15 publications

Allelic variations of RANKL/OPG signaling system are related to bone mineral density and in vivo gene expression

Allelic variations of RANKL/OPG signaling system are related to bone mineral density and in vivo gene expression

The putative cannabinoid receptor GPR55 affects osteoclast function in vitro and bone mass in vivo

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

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