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1.
Tissue Cell ; 88: 102412, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38776732

RESUMO

Tumor necrosis factor superfamily member 11 (TNFSF11), or receptor activator of nuclear factor-κB ligand (RANKL), is a crucial osteoclast-stimulating factor binding to RANK on osteoclast membranes. Mouse models are powerful tools for understanding the genetic mechanisms of related diseases. Here, we examined the utility of Tnfsf11 mutation in mice for understanding the mechanisms of bone remodeling and dysmorphology. The Tnfsf11gum mouse, discovered in 2011 at Jackson Laboratory, was used to study the genetic landscape associated with TNFSF11 inactivation in bone marrow tissues. Tnfsf11gum/+ and Tnfsf11+/+ mice were subjected to Micro-CT observation, ELISA analysis, histological evaluation, and massively-parallel mRNA sequencing (RNA-Seq) analysis. Tnfsf11gum/+ mice exhibited severe osteopetrotic changes in the bone marrow cavity, along with significantly lower serum RANKL levels and a reduced number of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts in the bone marrow compared to those in Tnfsf11+/+ mice. However, tooth eruption between Tnfsf11gum/+ and Tnfsf11+/+ mice did not differ. Furthermore, genes involved in osteoblast proliferation and differentiation, including Gli1, Slc35b2, Lrrc17, and Junb were differentially expressed. Heterozygous mutation of TNFSF11 was also associated with a slightly increased expression of genes involved in osteoclast proliferation and differentiation, including Tcirg1, Junb, Anxa2, and Atp6ap1. Overall, we demonstrate that single gene mutations in Tnfsf11 cause bone resorption instability without significantly altering the genes related to osteoblast and osteoclast activity in the bone marrow cavity, thus establishing an optimal resource as an experimental animal model for bone resorption in bone biology research.


Assuntos
Modelos Animais de Doenças , Osteoclastos , Osteopetrose , Ligante RANK , Animais , Osteopetrose/genética , Osteopetrose/patologia , Osteopetrose/metabolismo , Ligante RANK/metabolismo , Ligante RANK/genética , Camundongos , Osteoclastos/metabolismo , Osteoclastos/patologia , Mutação
2.
Calcif Tissue Int ; 115(1): 85-96, 2024 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-38733412

RESUMO

Autosomal dominant osteopetrosis type 2 (ADO2) is a rare inherited bone disorder characterised by dense but brittle bones. It displays striking phenotypic variability, with the most severe symptoms, including blindness and bone marrow failure. Disease management largely relies on symptomatic treatment since there is no safe and effective treatment. Most ADO2 cases are caused by heterozygous loss-of-function mutations in the CLCN7 gene, which encodes an essential Cl-/H+ antiporter for proper bone resorption by osteoclasts. Thus, siRNA-mediated silencing of the mutant allele is a promising therapeutic approach, but targeting bone for first-in-human translation remains challenging. Here, we demonstrate the utility of silicon-stabilised hybrid lipid nanoparticles (sshLNPs) as a next-generation nucleic acid nanocarrier capable of delivering allele-specific siRNA to bone. Using a Clcn7G213R knock-in mouse model recapitulating one of the most common human ADO2 mutations and based on the 129S genetic background (which produces the most severe disease phenotype amongst current models), we show substantial knockdown of the mutant allele in femur when siRNA targeting the pathogenic variant is delivered by sshLNPs. We observed lower areal bone mineral density in femur and reduced trabecular thickness in femur and tibia, when siRNA-loaded sshLNPs were administered subcutaneously (representing the most relevant administration route for clinical adoption and patient adherence). Importantly, sshLNPs have improved stability over conventional LNPs and enable 'post hoc loading' for point-of-care formulation. The treatment was well tolerated, suggesting that sshLNP-enabled gene therapy might allow successful clinical translation of essential new treatments for ADO2 and potentially other rare genetic bone diseases.


Assuntos
Alelos , Canais de Cloreto , Nanopartículas , Osteopetrose , Fenótipo , RNA Interferente Pequeno , Animais , Canais de Cloreto/genética , Osteopetrose/genética , Osteopetrose/terapia , Camundongos , RNA Interferente Pequeno/administração & dosagem , RNA Interferente Pequeno/genética , Osso e Ossos/metabolismo , Osso e Ossos/efeitos dos fármacos , Modelos Animais de Doenças
3.
JBJS Case Connect ; 14(2)2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38728525

RESUMO

CASE: Two patients with osteopetrosis underwent conversion total hip arthroplasty (THA) after failure of internal fixation due to hip fractures. We experienced challenges, including difficulty of hardware removal, remaining of previous broken screws in the canal, difficulty in finding the femoral canal, and an intraoperative acetabulum fracture. Despite complications, both patients achieved satisfactory functional outcome after surgery at the latest follow-up. CONCLUSION: Our cases showed that previous hip fracture and failed internal fixation make conversion THA more complex and unpredictable in patients with osteopetrosis. This in turn underscores the critical need for advanced preoperative planning, intraoperative flexibility, and meticulous postoperative care.


Assuntos
Artroplastia de Quadril , Osteopetrose , Humanos , Artroplastia de Quadril/métodos , Osteopetrose/cirurgia , Osteopetrose/complicações , Feminino , Fraturas do Quadril/cirurgia , Masculino , Pessoa de Meia-Idade , Fixação Interna de Fraturas/métodos , Idoso
4.
Pediatr Transplant ; 28(3): e14689, 2024 May.
Artigo em Inglês | MEDLINE | ID: mdl-38655726

RESUMO

BACKGROUND: Osteopetrosis is a group of geneticall heterogeneous disorders resulting from impaired osteoclast function and bone resorption. The identification of specific genetic mutations can yield important prognostic and therapeutic implications. Herein, we present the diagnosis and successful application of hematopoietic stem cell transplantation (HSCT) in a patient with osteopetrosis caused by carbonic anhydrase II deficiency (Intermediate osteopetrosis). CASE PRESENTATION: Herein, we describe a 2.5-year-old male patient born to consanguineous parents who presented at 8-month-old with hydrocephaly, brain shunt, and developmental delay. Later at 9 months old, he was found to have eye disorder such as nystagmus, fracture of the elbow, abnormal skeletal survey, normal cell blood count (CBC), and severe hypocellularity in the bone marrow. Further evaluation showed renal tubular acidosis type 2. Whole-exome sequencing revealed a pathogenic homozygous variant in intron 2 of the carbonic anhydrase 2 gene (CA2) gene (c.232 + 1 G>T). The diagnosis of intermediate autosomal recessive osteopetrosis was established, and allogenic HSCT from his mother, a full-matched related donor (MRD), was planned. The conditioning regimen included Busulfan, Fludarabine, and Rabbit anti-thymocyte globulin. Cyclosporine and Mycophenolate Mofetil were used for graft-versus-host-disease prophylaxis. He Engrafted on day +13, and 95% chimerism was achieved. He is currently doing well without immunosuppressive therapy, now 12 months post HSCT, with normal calcium level and improving visual quality and FISH analysis revealed complete donor chimerism. DISCUSSION: HSCT could be a promising curative treatment for intermediate osteopetrosis and can provide long-term survival. Ongoing challenges in various aspects of HSCT remain to be addressed.


Assuntos
Anidrases Carbônicas/deficiência , Transplante de Células-Tronco Hematopoéticas , Osteopetrose , Distúrbios Congênitos do Ciclo da Ureia , Humanos , Masculino , Osteopetrose/genética , Osteopetrose/terapia , Pré-Escolar , Irã (Geográfico) , Anidrase Carbônica II/genética , Anidrase Carbônica II/deficiência , Acidose Tubular Renal/genética , Acidose Tubular Renal/terapia , Transplante Homólogo
5.
Eur J Med Genet ; 69: 104936, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38593953

RESUMO

Osteopetrosis refers to a group of related rare bone diseases characterized by a high bone mass due to impaired bone resorption by osteoclasts. Despite the high bone mass, skeletal strength is compromised and the risk of fracture is high, particularly in the long bones. Osteopetrosis was classically categorized by inheritance pattern into autosomal recessive forms (ARO), which are severe and diagnosed within the first years of life, an intermediate form and an autosomal dominant (ADO) form; the latter with variable clinical severity and typically diagnosed during adolescence or in young adulthood. Subsequently, the AD form was shown to be a result of mutations in the gene CLCN7 encoding for the ClC-7 chloride channel). Traditionally, the diagnosis of osteopetrosis was made on radiograph appearance alone, but recent molecular and genetic advances have enabled a greater fidelity in classification of osteopetrosis subtypes. In the more severe ARO forms (e.g., malignant infantile osteopetrosis MIOP) typical clinical features have severe consequences and often result in death in early childhood. Major complications of ADO are atypical fractures with delay or failure of repair and challenge in orthopedic management. Bone marrow failure, dental abscess, deafness and visual loss are often underestimated and neglected in relation with lack of awareness and expertise. Accordingly, the care of adult patients with osteopetrosis requires a multidisciplinary approach ideally in specialized centers. Apart from hematopoietic stem cell transplantation in certain infantile forms, the treatment of patients with osteopetrosis, has not been standardized and remains supportive. Further clinical studies are needed to improve our knowledge of the natural history, optimum management and impact of osteopetrosis on the lives of patients living with the disorder.


Assuntos
Osteoclastos , Osteopetrose , Osteopetrose/genética , Osteopetrose/patologia , Humanos , Osteoclastos/patologia , Adulto , Canais de Cloreto/genética , Mutação
6.
Pediatr Radiol ; 54(7): 1105-1115, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38483591

RESUMO

Osteopetrosis describes several types of rare sclerosing bone dysplasias of varying clinical and radiographic severity. The classic autosomal dominant subtype emerges most often in adolescence but can present from infancy through adulthood. The autosomal recessive osteopetrosis, or "malignant infantile osteopetrosis," presents in infancy with a grimmer prognosis, though the autosomal dominant forms (often mislabeled as "benign") actually can have life-threatening consequences as well. Often osteopetrosis is detected due to skeletal findings on radiographs performed to evaluate injury or as an incidental finding during evaluation for illness. Given the varied phenotypic severity and presentations at different ages, radiologists play an integral role in the care of these patients both in diagnosis and in clinical evaluation and monitoring. A deeper understanding of the underlying genetic basis of the disease can aid in the radiologist in diagnosis and in anticipation of unique complications. An overview of current clinical management is also discussed.


Assuntos
Osteopetrose , Humanos , Osteopetrose/diagnóstico por imagem , Criança , Diagnóstico Diferencial , Adolescente , Lactente
7.
Stem Cell Res ; 76: 103330, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38335662

RESUMO

Infantile Malignant Osteopetrosis (IMO) is a rare, severe autosomal recessive form of osteopetrosis. Here, the peripheral blood mononuclear cells (PBMCs) extracted from a patient with IMO carrying a compound heterozygous mutation in T cell immune regulator 1, ATPase H + transporting V0 subunit a3 (TCIRG1) gene (c.242delC; c.1114C > T) were successfully reprogrammed using Sendai virus encoding the four Yamanaka factors. The generated hiPSCs, IMO-hiPSCs, displayed typical embryonic stem cell-like morphology and were verified by expression of pluripotency markers such as OCT4, SOX2, NANOG, TRA-1-60 and SSEA4, as well as in vivo and in vitro differentiation into derivatives of three germ layers.


Assuntos
Células-Tronco Pluripotentes Induzidas , Osteopetrose , ATPases Vacuolares Próton-Translocadoras , Humanos , Células-Tronco Pluripotentes Induzidas/metabolismo , Osteopetrose/metabolismo , Leucócitos Mononucleares/metabolismo , Mutação , Genes Homeobox , Diferenciação Celular , ATPases Vacuolares Próton-Translocadoras/genética
8.
J Mol Med (Berl) ; 102(4): 435-452, 2024 04.
Artigo em Inglês | MEDLINE | ID: mdl-38363329

RESUMO

Osteocalcin (OC) is the most abundant non-collagenous and osteoblast-secreted protein in bone. It consists of two forms such as carboxylated OC (cOC) and undercarboxylated OC (ucOC). While cOC promotes bone mineralization and increases bone strength, ucOC is regarded an endocrinologically active form that may have several functions in multiple end organs and tissues. Total OC (tOC) includes both of these forms (cOC and ucOC) and is considered a marker of bone turnover in clinical settings. Most of the data on OC is limited to preclinical studies and therefore may not accurately reflect the situation in clinical conditions. For the stated reason, the aim of this review was not only to summarize current knowledge of all forms of OC and characterize its role in diabetes mellitus, osteoporosis, osteopetrosis, inflammatory joint diseases, but also to provide new interpretations of its involvement in the management and treatment of aforementioned diseases. In this context, special emphasis was placed on available clinical trials. Significantly lower levels of tOC and ucOC could be associated with the risk of type 2 diabetes mellitus. On the contrary, tOC level does not seem to be a good indicator of high bone turnover status in postmenopausal osteoporosis, osteoarthritis and rheumatoid arthritis. The associations between several pharmacological drugs used to treat all disorders mentioned above and OC levels have also been provided. From this perspective, OC may serve as a medium through which certain medications can influence glucose metabolism, body weight, adiponectin secretion, and synovial inflammation.


Assuntos
Diabetes Mellitus Tipo 2 , Artropatias , Osteopetrose , Osteoporose , Humanos , Diabetes Mellitus Tipo 2/tratamento farmacológico , Osteocalcina/metabolismo , Osteoporose/tratamento farmacológico , Osteoporose/etiologia , Biomarcadores
9.
Calcif Tissue Int ; 114(4): 419-429, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-38300304

RESUMO

Autosomal Dominant Osteopetrosis type II (ADO2) is a rare bone disease of impaired osteoclastic bone resorption that usually results from heterozygous missense mutations in the chloride channel 7 (CLCN7) gene. We previously created mouse models of ADO2 (p.G213R) with one of the most common mutations (G215R) as found in humans and demonstrated that this mutation in mice phenocopies the human disease of ADO2. Previous studies have shown that roflumilast (RF), a selective phosphodiesterase 4 (PDE4) inhibitor that regulates the cAMP pathway, can increase osteoclast activity. We also observed that RF increased bone resorption in both wild-type and ADO2 heterozygous osteoclasts in vitro, suggesting it might rescue bone phenotypes in ADO2 mice. To test this hypothesis, we administered RF-treated diets (0, 20 and 100 mg/kg) to 8-week-old ADO2 mice for 6 months. We evaluated bone mineral density and bone micro-architecture using longitudinal in-vivo DXA and micro-CT at baseline, and 6-, 12-, 18-, and 24-week post-baseline time points. Additionally, we analyzed serum bone biomarkers (CTX, TRAP, and P1NP) at baseline, 12-, and 24-week post-baseline. Our findings revealed that RF treatment did not improve aBMD (whole body, femur, and spine) and trabecular BV/TV (distal femur) in ADO2 mice compared to the control group treated with a normal diet. Furthermore, we did not observe any significant changes in serum levels of bone biomarkers due to RF treatment in these mice. Overall, our results indicate that RF does not rescue the osteopetrotic bone phenotypes in ADO2 heterozygous mice.


Assuntos
Aminopiridinas , Benzamidas , Reabsorção Óssea , Osteopetrose , Inibidores da Fosfodiesterase 4 , Humanos , Animais , Camundongos , Inibidores da Fosfodiesterase 4/farmacologia , Inibidores da Fosfodiesterase 4/uso terapêutico , Inibidores da Fosfodiesterase 4/metabolismo , Fenótipo , Biomarcadores , Osteoclastos/metabolismo , Reabsorção Óssea/metabolismo , Osteopetrose/genética , Canais de Cloreto/genética , Ciclopropanos
10.
J Immunol ; 212(7): 1081-1093, 2024 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-38380993

RESUMO

Arthritis causes Fos-like 2 (Fosl2) inactivation, and various immune cells contribute to its pathogenesis. However, little is known about the role of Fosl2 in hematopoiesis and the possible pathological role of Fosl2 inactivation in the hematopoietic system in arthritis. In this study, we show that Fosl2 maintains hematopoietic stem cell (HSC) quiescence and differentiation while controlling the inflammatory response via macrophages. Fosl2-specific deletion in the hematopoietic system caused the expansion of HSCs and myeloid cell growth while affecting erythroid and B cell differentiation. Fosl2 inactivation enhanced macrophage M1 polarization and stimulated proinflammatory cytokines and myeloid growth factors, skewing HSCs toward myeloid cell differentiation, similar to hematopoietic alterations in arthritic mice. Loss of Fosl2 mediated by Vav-iCre also displays an unexpected deletion in embryonic erythro-myeloid progenitor-derived osteoclasts, leading to osteopetrosis and anemia. The reduced bone marrow cellularity in Vav-iCreFosl2f/f mice is a consequence of the reduced bone marrow space in osteopetrotic mice rather than a direct role of Fosl2 in hematopoiesis. Thus, Fosl2 is indispensable for erythro-myeloid progenitor-derived osteoclasts to maintain the medullary cavity to ensure normal hematopoiesis. These findings improve our understanding of the pathogenesis of bone-destructive diseases and provide important implications for developing therapeutic approaches for these diseases.


Assuntos
Antígeno 2 Relacionado a Fos , Células-Tronco Hematopoéticas , Osteopetrose , Animais , Camundongos , Artrite/patologia , Transtornos da Insuficiência da Medula Óssea/patologia , Diferenciação Celular , Hematopoese/genética , Osteopetrose/genética , Osteopetrose/patologia , Antígeno 2 Relacionado a Fos/genética
11.
J Clin Endocrinol Metab ; 109(7): 1726-1732, 2024 Jun 17.
Artigo em Inglês | MEDLINE | ID: mdl-38261998

RESUMO

CONTEXT: Autosomal dominant osteopetrosis (ADO) is a rare genetic disorder resulting from impaired osteoclastic bone resorption. Clinical manifestations frequently include fractures, osteonecrosis (particularly of the jaw or maxilla), osteomyelitis, blindness, and/or bone marrow failure. ADO usually results from heterozygous missense variants in the Chloride Channel 7 gene (CLCN7) that cause disease by a dominant negative mechanism. Variants in the T-cell immune regulator 1 gene (TCIRG1) are commonly identified in autosomal recessive osteopetrosis but have only been reported in 1 patient with ADO. CASE DESCRIPTION: Here, we report 3 family members with a single heterozygous missense variant (p.Gly579Arg) in TCIRG1 who have a phenotype consistent with ADO. Three of 5 protein prediction programs suggest this variant likely inhibits the function of TCIRG1. CONCLUSION: This is the first description of adult presentation of ADO caused by a TCIRG1 variant. Similar to families with ADO from CLCN7 mutations, this variant in TCIRG1 results in marked phenotype variability, with 2 subjects having severe disease and the third having very mild disease. This family report implicates TCIRG1 missense mutations as a cause of ADO and demonstrates that the marked phenotypic variability in ADO may extend to disease caused by TCIRG1 missense mutations.


Assuntos
Mutação de Sentido Incorreto , Osteopetrose , Linhagem , Humanos , Osteopetrose/genética , Masculino , Feminino , Adulto , ATPases Vacuolares Próton-Translocadoras/genética , Fenótipo , Pessoa de Meia-Idade , Genes Dominantes
12.
Skeletal Radiol ; 53(4): 817-820, 2024 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-37672091

RESUMO

A 5-month-old infant with bone findings on x-ray presented an apparent contradiction including findings of both diffusely dense bones and rickets in the context of a history and laboratory investigation that suggested leukemia. Next generation gene panel sequencing revealed a TCIRG1 mutation which is consistent with autosomal recessive osteopetrosis. The paradoxical x-ray findings underscore a recently elucidated mechanism for the pathogenesis of a TCIRG mutation. This case highlights the importance of recognizing this radiographic, seeming contradictory, association in the context of a confusing clinical presentation. Failure to recognize this pattern promptly may lead to a delay in diagnosis, thus potentially permanent organ failure.


Assuntos
Osteopetrose , Raquitismo , ATPases Vacuolares Próton-Translocadoras , Lactente , Humanos , Osteopetrose/diagnóstico por imagem , Osteopetrose/genética , Osteopetrose/patologia , Raquitismo/diagnóstico por imagem , Radiografia , Mutação , ATPases Vacuolares Próton-Translocadoras/genética
13.
J Pediatr Orthop ; 44(1): e69-e72, 2024 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-37728079

RESUMO

BACKGROUND: The aim of this study is to determine the demographic data, fracture treatment methods, and medical treatments of patients diagnosed with osteopetrosis in the national registry. METHODS: Patients with International Classification of Diseases (ICD)-10 code Q78.2 for osteopetrosis between January 1, 2016 and April 11, 2023 were retrospectively reviewed. Data on sex, age at time of diagnosis, fracture history, mortality, and use of medications were evaluated for all patients. In addition, open reduction and internal fixation, closed reduction and internal fixation, closed reduction and casting, and conservative treatment methods were noted. The number of patients requiring deformity surgery was determined. The incidence and prevalence of osteopetrosis were also calculated in this cross-sectional study. RESULTS: A total of 476 patients diagnosed with osteopetrosis were identified. The mean age at time of diagnosis of these patients was 5.79 ± 5.43 years. A total of 101 patients died. As the age at diagnosis decreased, the mortality rate of the patients increased with statistical significance ( P <0.001). A total of 192 fractures were seen in 121 osteopetrosis patients in this study. Femur fractures were most common among these patients with osteopetrosis. A history of fracture was statistically significantly less common in patients using a combination of vitamin D + calcium compared with patients not using such medication ( P <0.001). In this 7-year cross-sectional study, the incidence was found to be 1 in 416,000 and the prevalence was 0.00199% in the population under 18 years of age. CONCLUSION: Younger age at diagnosis is associated with higher mortality in patients with osteopetrosis. In addition, the combination of vitamin D and calcium were associated with lower fracture incidence. LEVEL OF EVIDENCE: Prognostic Level II.


Assuntos
Fraturas do Fêmur , Osteopetrose , Humanos , Adolescente , Lactente , Pré-Escolar , Criança , Estudos Retrospectivos , Osteopetrose/epidemiologia , Osteopetrose/terapia , Osteopetrose/complicações , Estudos Transversais , Cálcio , Turquia , Fixação Interna de Fraturas/métodos , Fraturas do Fêmur/cirurgia , Vitamina D
14.
Biomolecules ; 13(12)2023 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-38136669

RESUMO

ClC-7 is a ubiquitously expressed voltage-gated Cl-/H+ exchanger that critically contributes to lysosomal ion homeostasis. Together with its ß-subunit Ostm1, ClC-7 localizes to lysosomes and to the ruffled border of osteoclasts, where it supports the acidification of the resorption lacuna. Loss of ClC-7 or Ostm1 leads to osteopetrosis accompanied by accumulation of storage material in lysosomes and neurodegeneration. Interestingly, not all osteopetrosis-causing CLCN7 mutations from patients are associated with a loss of ion transport. Some rather result in an acceleration of voltage-dependent ClC-7 activation. Recently, a gain-of-function variant, ClC-7Y715C, that yields larger ion currents upon heterologous expression, was identified in two patients with neurodegeneration, organomegaly and albinism. However, neither the patients nor a mouse model that carried the equivalent mutation developed osteopetrosis, although expression of ClC-7Y715C induced the formation of enlarged intracellular vacuoles. Here, we investigated how, in transfected cells with mutant ClC-7, the substitution of this tyrosine impinged on the morphology and function of lysosomes. Combinations of the tyrosine mutation with mutations that either uncouple Cl- from H+ counter-transport or strongly diminish overall ion currents were used to show that increased ClC-7 Cl-/H+ exchange activity is required for the formation of enlarged vacuoles by membrane fusion. Degradation of endocytosed material was reduced in these compartments and resulted in an accumulation of lysosomal storage material. In cells expressing the ClC-7 gain-of-function mutant, autophagic clearance was largely impaired, resulting in a build-up of autophagic material.


Assuntos
Osteopetrose , Camundongos , Animais , Humanos , Osteopetrose/genética , Osteopetrose/metabolismo , Mutação com Ganho de Função , Mutação , Lisossomos/metabolismo , Tirosina/metabolismo , Canais de Cloreto/genética , Canais de Cloreto/metabolismo
15.
J Physiol ; 601(24): 5635-5653, 2023 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-37937509

RESUMO

ClC-6 and ClC-7 are closely related, intracellular Cl- /H+ antiporters belonging to the CLC family of channels and transporters. They localize to acidic late endosomes and lysosomes and probably function in ionic homeostasis of these contiguous compartments. ClC-7 transport function requires association with the accessory protein Ostm1, whereas ClC-6 transport does not. To elucidate their roles in endo-lysosomes, we measured Cl- - and pH-dependences of over-expressed wild-type ClC-6 and ClC-7, as well as disease-associated mutants, using high-resolution recording protocols. Lowering extracellular Cl- (corresponding to luminal Cl- in endo-lysosomes) reduced ClC-6 currents, whereas it increased transport activity of ClC-7/Ostm1. Low extracellular Cl- activated ClC-7/Ostm 1 under acidic extracellular conditions, as well as under conditions of low intracellular chloride. Activation is conserved in ClC-7Y713C , a variant displaying disrupted PI(3,5)P2 inhibition. Detailed biophysical analysis of disease-associated ClC-6 and ClC-7 gain-of-function (GoF) variants, ClC-6Y553C and ClC-7Y713C , and the ClC-7Y577C and ClC-6Y781C correlates, identified additional functional nuances distinguishing ClC-6 and ClC-7. ClC-7Y577C recapitulated GoF produced by ClC-6Y553C . ClC-6Y781C displayed transport activation qualitatively similar to ClC-7Y713C , although current density did not differ from that of wild-type ClC-6. Finally, rClC-7R760Q , homologous to hClC-7R762Q , an osteopetrosis variant with fast gating kinetics, appeared indifferent to extracellular Cl- , identifying altered Cl- sensitivity as a plausible mechanism underlying disease. Collectively, the present studies underscore the distinct roles of ClC-6 and ClC-7 within the context of their respective localization to late endosomes and lysosomes. In particular, we suggest the atypical inhibition of ClC-7 by luminal Cl- serves to limit excessive intraluminal Cl- accumulation. KEY POINTS: ClC-6 and ClC-7 are late endosomal and lysosomal 2 Cl- /1 H+ exchangers, respectively. When targeted to the plasma membrane, both activate slowly at positive voltages. ClC-6 activity is decreased in low extracellular (i.e. luminal) chloride, whereas ClC-7 is activated by low luminal chloride, even at acidic pH. The functional gain-of-function phenotypes of the ClC-6 and ClC-7 disease mutations ClC-6Y553C and ClC-7Y715C are maintained when introduced in their respective homologues, ClC-7Y577C and ClC-6Y781C , with all mutations retaining chloride dependence of the respective wild type (WT). An osteopetrosis mutation of ClC-7 displaying fast gating kinetics (R762Q) was less sensitive to extracellular chloride compared to WT. The opposing substrate dependences of ClC-6 and ClC-7 Cl- / H+ exchangers point to non-overlapping physiological functions, leading us to propose that inhibition of ClC-7 by luminal chloride and protons serves to prevent osmotic stress imposed by hyper-accumulation of chloride.


Assuntos
Canais de Cloreto , Cloretos , Osteopetrose , Humanos , Canais de Cloreto/fisiologia , Cloretos/metabolismo , Homeostase , Lisossomos/metabolismo , Osteopetrose/metabolismo , Prótons
16.
Front Endocrinol (Lausanne) ; 14: 1258340, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37920250

RESUMO

Background: Osteosclerotic metaphyseal dysplasia (OSMD, OMIM 615198) is an extremely rare autosomal recessive osteopetrosis disorder resulting in a distinctive pattern of osteosclerosis of the metaphyseal margins of long tubular bones. To date, only thirteen cases have been reported (eight molecularly confirmed). Five homozygous sequence variants in the leucine-rich repeat kinase 1 (LRRK1) gene have been identified to cause OSMD. We present two male siblings with OSMD with a novel LRRK1 variant. Cases: The index case, now aged 6 years, was referred aged 9 months when diffuse sclerosis of the ribs and vertebral bodies, suggestive of osteopetrosis, was incidentally identified on a chest radiograph for suspected lower respiratory tract infection. Parents were consanguineous and of Pakistani origin. Further evaluation revealed developmental delay, nystagmus with bilateral optic nerve hypoplasia and severe visual impairment. Skeletal survey confirmed typical changes of OSMD, with widespread diffuse sclerosis and Erlenmeyer flask deformity of long bones. His older sibling, now aged 12 years, was 7 years at the time of referral and had similar clinical course and skeletal findings. Additionally, he had a chronic progressive osteonecrosis of the left mandible that required debridement, debulking and long-term antibiotics. Skeletal survey revealed findings similar to his sibling. Neither sibling had significant skeletal fractures or seizures. Unlike most previous reports suggesting sparing of the skull and lack of visual impairment, our patients had evidence of osteosclerosis of the cranium. Genetic screening for the common autosomal recessive and dominant pathogenic variants of osteopetrosis was negative. Whole Exome Sequencing (WES) followed by Sanger sequencing, identified a novel homozygous LRRK1 c.2506C>T p. (Gln836Ter) nonsense variant predicted to result in premature truncation of LRRK1 transcript. Conclusion: Our cases confirm the autosomal recessive inheritance and expand the spectrum of genotype and phenotype of OSMD reported in the literature. Increasing reports of LRRK1 variants in this phenotype raise the question of whether LRRK1 should be included in targeted osteopetrosis panels. Bone histology in previous cases has shown this to be an osteoclast rich form of osteopetrosis raising the possibility that haematopoietic stem cell transplantation may be an appropriate treatment modality.


Assuntos
Osteopetrose , Osteosclerose , Humanos , Masculino , Mutação , Nervo Óptico , Osteopetrose/complicações , Osteopetrose/genética , Osteosclerose/complicações , Osteosclerose/genética , Osteosclerose/diagnóstico , Proteínas Serina-Treonina Quinases/genética , Costelas , Esclerose , Transtornos da Visão , Criança
17.
BMC Oral Health ; 23(1): 940, 2023 11 28.
Artigo em Inglês | MEDLINE | ID: mdl-38017429

RESUMO

BACKGROUND: Osteopetrosis comprises a group of inherited disorders that are rare and result in abnormal bone structure. Bone remodeling is extremely inhibited because osteoclasts are nonfunctional or lacking. This condition causes overgrowth of bone with disappearance of the bone marrow, leading to aplastic anemia; obstruction of nerve passages in the skull leads to blindness and often hearing impairment. In most cases, osteopetrosis results in oral complications such as tooth deformation, hypomineralization, and delayed or absent tooth eruption. The only curative treatment is hematopoietic stem cell transplantation (HSCT). The main treatment of the oral complications during childhood and adolescence consists in protecting the erupted teeth against caries disease through prophylactic treatment aimed at optimal oral hygiene through frequent regular dental visits throughout life. Many patients with osteopetrosis require major oral rehabilitation to treat complications of the disease. Improved results of HSCT increase the likelihood that dental professionals will encounter patients with osteopetrosis. CASE PRESENTATION: In this case report, we show that individuals with osteopetrosis who have severe oral complications can be treated successfully if they are treated for osteopetrosis at an early age. The boy had his dental care in pedodontics, and regular multidisciplinary meetings were held for future treatment planning. At the age of 15, he was then referred for rehabilitation. The initial evaluations revealed no further growth in the alveolar bone. The rehabilitation was done stepwise, with extraction of malformed and malpositioned teeth. Initially, the patient received a removable partial denture followed by reconstruction of the width of the alveolar process, titanium implants, temporary fixed bridges, and finally screw-retained titanium-ceramic bridges with titanium frames for the upper and lower jaws. CONCLUSIONS: The three-year follow-up after loading indicated a stable marginal bone level and optimal oral hygiene as a result of frequent professional oral hygiene care. The patient showed no signs of symptoms from the temporomandibular joint and has adapted to the new jaw relation without any functional or phonetical issues.


Assuntos
Cárie Dentária , Implantes Dentários , Osteopetrose , Anormalidades Dentárias , Masculino , Adolescente , Humanos , Osteopetrose/complicações , Osteopetrose/cirurgia , Titânio , Prótese Parcial Fixa , Prótese Dentária Fixada por Implante
18.
Zhonghua Er Ke Za Zhi ; 61(11): 1038-1042, 2023 Nov 02.
Artigo em Chinês | MEDLINE | ID: mdl-37899344

RESUMO

Objective: To investigate the clinical presentation and genetic characteristics of malignant infantile osteopetrosis. Methods: This was a retrospective case study. Thirty-seven children with malignant infantile osteopetrosis admitted into Beijing Children's Hospital from January 2013 to September 2022 were enrolled in this study. According to the gene mutations, the patients were divided into the CLCN7 group and the TCIRG1 group. Clinical characteristics, laboratory tests, and prognosis were compared between two groups. Wilcoxon test or Fisher exact test were used in inter-group comparison. The survival rate was estimated with the Kaplan-Meier method and the Log-Rank test was used to compare the difference in survival between groups. Results: Among the 37 cases, there were 22 males and 15 females. The age of diagnosis was 0.5 (0.2, 1.0) year. There were 13 patients (35%) and 24 patients (65%) with mutations in CLCN7 and TCIRGI gene respectively. Patients in the CLCN7 group had an older age of diagnosis than those in the TCIRGI group (1.2 (0.4, 3.6) vs. 0.4 (0.2, 0.6) years, Z=-2.60, P=0.008). The levels of serum phosphorus (1.7 (1.3, 1.8) vs. 1.1 (0.8, 1.6) mmol/L, Z=-2.59, P=0.010), creatine kinase isoenzyme (CK-MB) (457 (143, 610) vs. 56 (37, 82) U/L, Z=-3.38, P=0.001) and the level of neutrophils (14.0 (9.9, 18.1) vs. 9.2 (6.7, 11.1) ×109/L, Z=-2.07, P=0.039) at diagnosis were higher in the CLCN7 group than that in the TCIRG1 group. However, the level of D-dimer in the CLCN7 group was lower than that in the TCIRGI group (2.7 (1.0, 3.1) vs. 6.3 (2.5, 9.7) µg/L, Z=2.83, P=0.005). After hematopoietic stem cell transplantation, there was no significant difference in 5-year overall survival rate between the two groups (92.3%±7.4% vs. 83.3%±7.6%, χ²=0.56, P=0.456). Conclusions: TCIRGI gene mutations are more common in children with osteopetrosis. Children with TCIRGI gene mutations have younger age, lower levels of phosphorus, CK-MB, and neutrophils and higher level of D-dimer at the onset. After hematopoietic stem cell transplantation, patients with CLCN7 or TCIRGI gene mutations have similar prognosis.


Assuntos
Osteopetrose , ATPases Vacuolares Próton-Translocadoras , Criança , Masculino , Feminino , Humanos , Osteopetrose/diagnóstico , Osteopetrose/genética , Osteopetrose/terapia , Estudos Retrospectivos , Prognóstico , Genes Recessivos , Fósforo , Canais de Cloreto/genética , ATPases Vacuolares Próton-Translocadoras/genética
19.
BMJ Case Rep ; 16(10)2023 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-37907307

RESUMO

Osteopetrosis encompasses a spectrum of conditions marked by heightened bone density due to faulty osteoclast-mediated bone resorption, leading to an accumulation of immature bone and thickened cortical structures. This condition gives rise to bone fragility, blood cell irregularities, nerve entrapment and growth challenges, all stemming from disrupted bone remodelling. Craniofacial distinctiveness, encompassing anomalies in the skull and jaw, is a frequent occurrence. Osteopetrosis presents a range of clinical signs, including facial and dental anomalies. The diagnostic process involves thorough clinical and radiological assessments, often obviating the need for genetic testing. Interestingly, few prior reports have delved into the specifics of craniofacial and dental issues in osteopetrosis. The presented case showcases rare occurrence of maxillary osteomyelitis. The diagnosis was established through a combination of history, clinical, radiographic and laboratory findings. The patient declined surgical intervention, leading to the implementation of conservative management involving regular irrigation alongside systemic antibiotic therapy.


Assuntos
Osteomielite , Osteopetrose , Humanos , Feminino , Osteopetrose/complicações , Osteopetrose/diagnóstico por imagem , Osteomielite/diagnóstico , Osteomielite/diagnóstico por imagem , Maxila , Crânio , Densidade Óssea
20.
Int J Mol Sci ; 24(18)2023 Sep 08.
Artigo em Inglês | MEDLINE | ID: mdl-37762144

RESUMO

Osteopetrosis is a rare inherited disease caused by osteoclast failure, resulting in increasing bone density in humans. Patients with osteopetrosis possess several dental and cranial complications. Since carbonic anhydrase II (CA-II) deficiency is a major cause of osteopetrosis, CA-II activators might be an attractive potential treatment option for osteopetrosis patients. We conducted comprehensive label-free quantitative proteomics analysis on Fluconazole-treated Dental Pulp Mesenchymal Stem/Stromal Cells from CA-II-Deficient Osteopetrosis Patients. We identified 251 distinct differentially expressed proteins between healthy subjects, as well as untreated and azole-treated derived cells from osteopetrosis patients. Twenty-six (26) of these proteins were closely associated with osteogenesis and osteopetrosis disease. Among them are ATP1A2, CPOX, Ap2 alpha, RAP1B and some members of the RAB protein family. Others include AnnexinA1, 5, PYGL, OSTF1 and PGAM4, all interacting with OSTM1 in the catalytic reactions of HCO3 and the Cl- channel via CAII regulation. In addition, the pro-inflammatory/osteoclast regulatory proteins RACK1, MTSE, STING1, S100A13, ECE1 and TRIM10 are involved. We have identified proteins involved in osteogenic and immune metabolic pathways, including ERK 1/2, phosphatase and ATPase, which opens the door for some CA activators to be used as an alternative drug therapy for osteopetrosis patients. These findings propose that fluconazole might be a potential treatment agent for CAII- deficient OP patients. Altogether, our findings provide a basis for further work to elucidate the clinical utility of azole, a CA activator, as a therapeutic for OP.


Assuntos
Células-Tronco Mesenquimais , Osteopetrose , Humanos , Fluconazol/farmacologia , Fluconazol/uso terapêutico , Osteogênese , Polpa Dentária , Osteopetrose/tratamento farmacológico , Azóis , Redes e Vias Metabólicas , Proteínas rap de Ligação ao GTP
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