Osteopetrosis rescue upon RANKL administration to <i>Rankl</i>−<i>/</i>− mice: A new therapy for human RANKL-dependent ARO

Iacono, Nadia Lo; Blair, Harry C.; Poliani, Pietro Luigi; Marrella, Veronica; Ficara, Francesca; Cassani, Barbara; Facchetti, Fabio; Fontana, Elena; Guerrini, Matteo M.; Traggiai, Elisabetta; Schena, Francesca; Paulis, Marianna; Mantero, Stefano; Inforzato, Antonio; Valaperta, Serenella; Pangrazio, Alessandra; Crisafulli, Laura; Maina, Virginia; Kostenuik, Paul J.; Vezzoni, Paolo; Villa, Anna; Sobacchi, Cristina

doi:10.1002/jbmr.1712

Cited by 50 publications

(45 citation statements)

References 29 publications

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“…Furthermore, treatment of ARO with interferon g1b increases bone resorption, causing a reduction in trabecular bone area and an increase in bone marrow space (93). While treatment of ARO with RANKL recently was shown to improve the bone phenotype in mice and may prove effective in humans (94), specific pharmaceutical treatment of ADO has not been investigated systematically.…”

Section: Treatment Of Adomentioning

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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Section: Treatment Of Adomentioning

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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“…In an independent Rankl −/− model, Kim and colleagues described altered splenic microarchitecture and defects in B-cell follicle formation and in marginal zone integrity in the majority of Rankl −/− mice [53]. In the same model, red pulp expansion, white pulp reduction, and regions of intense extramedullary hematopoiesis in the spleen occur, together with severe reduction in thymic medulla [54]. Also in the Rankl tles / tles mouse, thymic hypoplasia and enlarged spleen have been reported [44].…”

Section: Rankl In the Immune Systemmentioning

confidence: 99%

RANKL Cytokine: From Pioneer of the Osteoimmunology Era to Cure for a Rare Disease

Iacono

Pangrazio

Abinun

et al. 2013

Clinical and Developmental Immunology

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Since its identification, the RANKL cytokine has been demonstrated to play a crucial role in bone homeostasis and lymphoid tissue organization. Genetic defects impairing its function lead to a peculiar form of autosomal recessive osteopetrosis (ARO), a rare genetic bone disease presenting early in life and characterized by increased bone density due to failure in bone resorption by the osteoclasts. Hematopoietic stem cell transplantation (HSCT) is the only option for the majority of patients affected by this life-threatening disease. However, the RANKL-dependent ARO does not gain any benefit from this approach, because the genetic defect is not intrinsic to the hematopoietic osteoclast lineage but rather to the mesenchymal one. Of note, we recently provided proof of concept of the efficacy of a pharmacological RANKL-based therapy to cure this form of the disease. Here we provide an overview of the diverse roles of RANKL in the bone and immune systems and review the clinical features of RANKL-deficient ARO patients and the results of our preclinical studies. We emphasize that these patients present a continuous worsening of the disease in the absence of a cure and strongly wish that the therapy we propose will be further developed.

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“…Mice immunization and treatment Rankl +/2 mice, a gift of Y. Choi (University of Pennsylvania), were maintained and genotyped, as described (8,13). A total of 10 8 fresh SRBCs was injected i.p.…”

Section: Methodsmentioning

confidence: 99%

“…In vivo RANKL blockade selectively and transiently depletes thymus Aire and tissue-restricted Ag expression, thus creating a window of defective negative selection (7). The administration of soluble RANKL in a Rankl 2/2 mouse model dramatically improves bone and hematopoietic defects (8), further providing the in vivo evidence of the unique role played by RANKL in linking bone homeostasis to the immune system (9)(10)(11). It is largely accepted that B cells have a close and multifaceted relationship with bone cells (12).…”

Section: T He Receptor Activator Of Nf-kb (Rank) Ligand (Rankl)mentioning

confidence: 99%

IL-10 Critically Modulates B Cell Responsiveness in Rankl−/− Mice

Marrella

Iacono

Fontana

et al. 2015

The Journal of Immunology

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The immune and the skeletal system are tightly interconnected, and B lymphocytes are uniquely endowed with osteo-interactive properties. In this context, receptor activator of NF-κB (RANK) ligand (RANKL) plays a pivotal role in lymphoid tissue formation and bone homeostasis. Although murine models lacking RANK or RANKL show defects in B cell number, the role of the RANKL–RANK axis on B physiology is still a matter of debate. In this study, we have characterized in detail B cell compartment in Rankl−/− mice, finding a relative expansion of marginal zone B cells, B1 cells, and plasma cells associated with increased Ig serum levels, spontaneous germinal center formation, and hyperresponse to CD40 triggering. Such abnormalities were associated with an increased frequency of regulatory B cells and augmented B cell–derived IL-10 production. Remarkably, in vivo IL-10-R blockade reduced T cell–triggered plasma cell differentiation and restrained the expansion of regulatory B cells. These data point to a novel role of the RANKL–RANK axis in the regulation of B cell homeostasis and highlight an unexpected link between IL-10 CD40 signaling and the RANKL pathway.

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Osteopetrosis rescue upon RANKL administration to Rankl−/− mice: A new therapy for human RANKL-dependent ARO

Cited by 50 publications

References 29 publications

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

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

RANKL Cytokine: From Pioneer of the Osteoimmunology Era to Cure for a Rare Disease

IL-10 Critically Modulates B Cell Responsiveness in Rankl−/− Mice

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