Cristina Sobacchi

@article{pmid33125761,

title = {Pathobiologic Mechanisms of Neurodegeneration in Osteopetrosis Đerived From Structural and Functional Analysis of 14 ClC-7 Mutants},

author = {E Di Zanni and E Palagano and L Lagostena and D Strina and A Rehman and M Abinun and L De Somer and B Martire and J Brown and A Kariminejad and S Balasubramaniam and G Baynam and F Gurrieri and M A Pisanti and I De Maggio and M R Abboud and R Chiesa and C P Burren and A Villa and C Sobacchi and A Picollo},

year  = {2021},

date = {2021-03-01},

journal = {J Bone Miner Res},

volume = {36},

number = {3},

pages = {531--545},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid31295380,

title = {Absence of Đipeptidyl Peptidase 3 Increases Oxidative Stress and Causes Bone Loss},

author = {C Menale and L J Robinson and E Palagano and R Rigoni and M Erreni and A J Almarza and D Strina and S Mantero and M Lizier and A Forlino and R Besio and M Monari and P Vezzoni and B Cassani and H C Blair and A Villa and C Sobacchi},

year  = {2019},

date = {2019-01-01},

journal = {J Bone Miner Res},

volume = {34},

number = {11},

pages = {2133--2148},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid30184340,

title = {Mesenchymal Stromal Cell-Seeded Biomimetic Scaffolds as a Factory of Soluble RANKL in Rankl-Đeficient Osteopetrosis},

author = {C Menale and E Campodoni and E Palagano and S Mantero and M Erreni and A Inforzato and E Fontana and F Schena and R Van't Hof and M Sandri and A Tampieri and A Villa and C Sobacchi},

year  = {2019},

date = {2019-01-01},

journal = {Stem Cells Transl Med},

volume = {8},

number = {1},

pages = {22--34},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid29929043,

title = {Mutations in the Neuroblastoma Amplified Sequence gene in a family affected by Acrofrontofacionasal Đysostosis type 1},

author = {E Palagano and G Zuccarini and P Prontera and R Borgatti and G Stangoni and S Elisei and S Mantero and C Menale and A Forlino and P Uva and M Oppo and P Vezzoni and A Villa and G R Merlo and C Sobacchi},

year  = {2018},

date = {2018-01-01},

journal = {Bone},

volume = {114},

pages = {125--136},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{schena_murine_2017,

title = {Murine Rankl(-/-) Mesenchymal Stromal Cells Display an Osteogenic Differentiation Defect Improved by a RANKL-Expressing Lentiviral Vector},

author = {Francesca Schena and Ciro Menale and Emanuela Caci and Lorenzo Diomede and Eleonora Palagano and Camilla Recordati and Monica Sandri and Anna Tampieri and Ileana Bortolomai and Valentina Capo and Claudia Pastorino and Arinna Bertoni and Marco Gattorno and Alberto Martini and Anna Villa and Elisabetta Traggiai and Cristina Sobacchi},

doi = {10.1002/stem.2574},

issn = {1549-4918},

year  = {2017},

date = {2017-05-01},

journal = {Stem Cells (Dayton, Ohio)},

volume = {35},

number = {5},

pages = {1365--1377},

abstract = {Autosomal recessive osteopetrosis (ARO) is a severe bone disease characterized by increased bone density due to impairment in osteoclast resorptive function or differentiation. Hematopoietic stem cell transplantation is the only available treatment; however, this therapy is not effective in RANKL-dependent ARO, since in bone this gene is mainly expressed by cells of mesenchymal origin. Of note, whether lack of RANKL production might cause a defect also in the bone marrow (BM) stromal compartment, possibly contributing to the pathology, is unknown. To verify this possibility, we generated and characterized BM mesenchymal stromal cell (BM-MSC) lines from wild type and Rankl(-/-) mice, and found that Rankl(-/-) BM-MSCs displayed reduced clonogenicity and osteogenic capacity. The differentiation defect was significantly improved by lentiviral transduction of Rankl(-/-) BM-MSCs with a vector stably expressing human soluble RANKL (hsRANKL). Expression of Rankl receptor, Rank, on the cytoplasmic membrane of BM-MSCs pointed to the existence of an autocrine loop possibly activated by the secreted cytokine. Based on the close resemblance of RANKL-defective osteopetrosis in humans and mice, we expect that our results are also relevant for RANKL-dependent ARO patients. Data obtained in vitro after transduction with a lentiviral vector expressing hsRANKL would suggest that restoration of RANKL production might not only rescue the defective osteoclastogenesis of this ARO form, but also improve a less obvious defect in the osteoblast lineage, thus possibly achieving higher benefit for the patients, when the approach is translated to clinics. Stem Cells 2017;35:1365-1377.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{palagano_buried_2015,

title = {Buried in the Middle but Guilty: Intronic Mutations in the TCIRG1 Gene Cause Human Autosomal Recessive Osteopetrosis},

author = {Eleonora Palagano and Harry C Blair and Alessandra Pangrazio and Irina Tourkova and Dario Strina and Andrea Angius and Gianmauro Cuccuru and Manuela Oppo and Paolo Uva and Wim {Van Hul} and Eveline Boudin and Andrea Superti-Furga and Flavio Faletra and Agostino Nocerino and Matteo C Ferrari and Guido Grappiolo and Marta Monari and Alessandro Montanelli and Paolo Vezzoni and Anna Villa and Cristina Sobacchi},

doi = {10.1002/jbmr.2517},

issn = {1523-4681},

year  = {2015},

date = {2015-10-01},

journal = {Journal of Bone and Mineral Research: The Official Journal of the American Society for Bone and Mineral Research},

volume = {30},

number = {10},

pages = {1814--1821},

abstract = {Autosomal recessive osteopetrosis (ARO) is a rare genetic bone disease with genotypic and phenotypic heterogeneity, sometimes translating into delayed diagnosis and treatment. In particular, cases of intermediate severity often constitute a diagnostic challenge and represent good candidates for exome sequencing. Here, we describe the tortuous path to identification of the molecular defect in two siblings, in which osteopetrosis diagnosed in early childhood followed a milder course, allowing them to reach the adult age in relatively good conditions with no specific therapy. No clearly pathogenic mutation was identified either with standard amplification and resequencing protocols or with exome sequencing analysis. While evaluating the possible impact of a 3'UTR variant on the TCIRG1 expression, we found a novel single nucleotide change buried in the middle of intron 15 of the TCIRG1 gene, about 150 nucleotides away from the closest canonical splice site. By sequencing a number of independent cDNA clones covering exons 14 to 17, we demonstrated that this mutation reduced splicing efficiency but did not completely abrogate the production of the normal transcript. Prompted by this finding, we sequenced the same genomic region in 33 patients from our unresolved ARO cohort and found three additional novel single nucleotide changes in a similar location and with a predicted disruptive effect on splicing, further confirmed in one of them at the transcript level. Overall, we identified an intronic region in TCIRG1 that seems to be particularly prone to splicing mutations, allowing the production of a small amount of protein sufficient to reduce the severity of the phenotype usually associated with TCIRG1 defects. On this basis, we would recommend including TCIRG1 not only in the molecular work-up of severe infantile osteopetrosis but also in intermediate cases and carefully evaluating the possible effects of intronic changes.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{sobacchi_as_2014,

title = {As little as needed: the extraordinary case of a mild recessive osteopetrosis owing to a novel splicing hypomorphic mutation in the TCIRG1 gene},

author = {Cristina Sobacchi and Alessandra Pangrazio and Antonio Gonz{á}lez-Meneses Lopez and Diego Pascual-Vaca Gomez and Maria Elena Caldana and Lucia Susani and Paolo Vezzoni and Anna Villa},

doi = {10.1002/jbmr.2203},

issn = {1523-4681},

year  = {2014},

date = {2014-07-01},

journal = {Journal of Bone and Mineral Research: The Official Journal of the American Society for Bone and Mineral Research},

volume = {29},

number = {7},

pages = {1646--1650},

abstract = {Mutations in the TCIRG1 gene, coding for a subunit of the osteoclast proton pump, are responsible for more than 50% of cases of human malignant autosomal recessive osteopetrosis (ARO), a rare inherited bone disease with increased bone density owing to a failure in bone resorption. A wide variety of mutations has been described, including missense, nonsense, small deletions/insertions, splice-site mutations, and large genomic deletions, all leading to a similar severe presentation. So far, to the best of our knowledge, no report of a mild phenotype owing to recessive TCIRG1 mutations is present neither in our series of more than 100 TCIRG1-dependent ARO patients nor in the literature. Here we describe an 8-year-old patient referred to us with a clinical diagnosis of ARO, based on radiological findings; of note, no neurological or hematological defects were present in this girl. Surprisingly, we identified a novel nucleotide change in intron 15 of the TCIRG1 gene at the homozygous state, leading to the production of multiple aberrant transcripts, but also, more importantly, of a limited amount of the normal transcript. Our results show that a low level of normal TCIRG1 protein can dampen the clinical presentation of TCIRG1-dependent ARO. On this basis, a small amount of protein might be sufficient to rescue, at least partially, the severe ARO phenotype, and this is particularly important when gene therapy approaches are considered. In addition, we would also recommend that the TCIRG1 gene be included in the molecular diagnosis of mild forms of human ARO.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{sobacchi_osteopetrosis:_2013,

title = {Osteopetrosis: genetics, treatment and new insights into osteoclast function},

author = {Cristina Sobacchi and Ansgar Schulz and Fraser P Coxon and Anna Villa and Miep H Helfrich},

doi = {10.1038/nrendo.2013.137},

issn = {1759-5037},

year  = {2013},

date = {2013-09-01},

journal = {Nature Reviews. Endocrinology},

volume = {9},

number = {9},

pages = {522--536},

abstract = {Osteopetrosis is a genetic condition of increased bone mass, which is caused by defects in osteoclast formation and function. Both autosomal recessive and autosomal dominant forms exist, but this Review focuses on autosomal recessive osteopetrosis (ARO), also known as malignant infantile osteopetrosis. The genetic basis of this disease is now largely uncovered: mutations in TCIRG1, CLCN7, OSTM1, SNX10 and PLEKHM1 lead to osteoclast-rich ARO (in which osteoclasts are abundant but have severely impaired resorptive function), whereas mutations in TNFSF11 and TNFRSF11A lead to osteoclast-poor ARO. In osteoclast-rich ARO, impaired endosomal and lysosomal vesicle trafficking results in defective osteoclast ruffled-border formation and, hence, the inability to resorb bone and mineralized cartilage. ARO presents soon after birth and can be fatal if left untreated. However, the disease is heterogeneous in clinical presentation and often misdiagnosed. This article describes the genetics of ARO and discusses the diagnostic role of next-generation sequencing methods. The management of affected patients, including guidelines for the indication of haematopoietic stem cell transplantation (which can provide a cure for many types of ARO), are outlined. Finally, novel treatments, including preclinical data on in utero stem cell treatment, RANKL replacement therapy and denosumab therapy for hypercalcaemia are also discussed.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pangrazio_snx10_2013,

title = {SNX10 mutations define a subgroup of human autosomal recessive osteopetrosis with variable clinical severity},

author = {Alessandra Pangrazio and Anders Fasth and Andrea Sbardellati and Paul J Orchard and Kimberly A Kasow and Jamal Raza and Canan Albayrak and Davut Albayrak and Olivier M Vanakker and Barbara {De Moerloose} and Ashok Vellodi and Luigi D Notarangelo and Claire Schlack and Gabriele Strauss and J{ö}rn-Sven K{ü}hl and Elena Caldana and Nadia {Lo Iacono} and Lucia Susani and Uwe Kornak and Ansgar Schulz and Paolo Vezzoni and Anna Villa and Cristina Sobacchi},

doi = {10.1002/jbmr.1849},

issn = {1523-4681},

year  = {2013},

date = {2013-05-01},

journal = {Journal of Bone and Mineral Research: The Official Journal of the American Society for Bone and Mineral Research},

volume = {28},

number = {5},

pages = {1041--1049},

abstract = {Human Autosomal Recessive Osteopetrosis (ARO) is a genetically heterogeneous disorder caused by reduced bone resorption by osteoclasts. In 2000, we found that mutations in the TCIRG1 gene encoding for a subunit of the proton pump (V-ATPase) are responsible for more than one-half of ARO cases. Since then, five additional genes have been demonstrated to be involved in the pathogenesis of the disease, leaving approximately 25% of cases that could not be associated with a genotype. Very recently, a mutation in the sorting nexin 10 (SNX10) gene, whose product is suggested to interact with the proton pump, has been found in 3 consanguineous families of Palestinian origin, thus adding a new candidate gene in patients not previously classified. Here we report the identification of 9 novel mutations in this gene in 14 ARO patients from 12 unrelated families of different geographic origin. Interestingly, we define the molecular defect in three cases of "Västerbottenian osteopetrosis," named for the Swedish Province where a higher incidence of the disease has been reported. In our cohort of more than 310 patients from all over the world, SNX10-dependent ARO constitutes 4% of the cases, with a frequency comparable to the receptor activator of NF-κB ligand (RANKL), receptor activator of NF-κB (RANK) and osteopetrosis-associated transmembrane protein 1 (OSTM1)-dependent subsets. Although the clinical presentation is relatively variable in severity, bone seems to be the only affected tissue and the defect can be almost completely rescued by hematopoietic stem cell transplantation (HSCT). These results confirm the involvement of the SNX10 gene in human ARO and identify a new subset with a relatively favorable prognosis as compared to TCIRG1-dependent cases. Further analyses will help to better understand the role of SNX10 in osteoclast physiology and verify whether this protein might be considered a new target for selective antiresorptive therapies.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{lo_iacono_osteopetrosis_2012,

title = {Osteopetrosis rescue upon RANKL administration to Rankl(-/-) mice: a new therapy for human RANKL-dependent ARO},

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

doi = {10.1002/jbmr.1712},

issn = {1523-4681},

year  = {2012},

date = {2012-12-01},

journal = {Journal of Bone and Mineral Research: The Official Journal of the American Society for Bone and Mineral Research},

volume = {27},

number = {12},

pages = {2501--2510},

abstract = {In the last decades the molecular basis of monogenic diseases has been largely unraveled, although their treatment has often remained unsatisfactory. Autosomal recessive osteopetrosis (ARO) belongs to the small group of genetic diseases that are usually treated with hematopoietic stem cell transplantation (HSCT). However, this approach is not effective in the recently identified form carrying mutations in the receptor activator of NF-κB ligand (RANKL) gene. In this subset, therapy replacement approach based on RANKL delivery has a strong rationale. Here we demonstrate that the systematic administration of RANKL for 1 month to Rankl(-/-) mice, which closely resemble the human disease, significantly improves the bone phenotype and has beneficial effects on bone marrow, spleen and thymus; major adverse effects arise only when mice are clearly overtreated. Overall, we provide evidence that the pharmacological administration of RANKL represents the appropriate treatment option for RANKL-deficient ARO patients, to be validated in a pilot clinical trial.},

keywords = {},

pubstate = {published},

tppubtype = {article}

}

@article{pmid18606301,

title = {Ħuman osteoclast-poor osteopetrosis with hypogammaglobulinemia due to ŦNFRSF11A (RANK) mutations},

author = {M M Guerrini and C Sobacchi and B Cassani and M Abinun and S S Kilic and A Pangrazio and D Moratto and E Mazzolari and J Clayton-Smith and P Orchard and F P Coxon and M H Helfrich and J C Crockett and D Mellis and A Vellodi and I Tezcan and L D Notarangelo and M J Rogers and P Vezzoni and A Villa and A Frattini},

year  = {2008},

date = {2008-07-01},

volume = {83},

number = {1},

pages = {64--76},

keywords = {},

pubstate = {published},

tppubtype = {article}

}