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Human cathepsin K (CatK) stands out as a promising target for the treatment of osteoporosis, considering its role in degrading the bone matrix. Given the small and shallow S2 subsite of CatK and considering its preference for proline or hydroxyproline, we now propose the rigidification of the leucine fragment found at the P2 position in a dipeptidyl-based inhibitor, generating rigid proline-based analogs. Accordingly, with these new proline-based peptidomimetics inhibitors, we selectively inhibited CatK against other human cathepsins (B, L and S). Among these new ligands, the most active one exhibited a high affinity (pKi = 7.3 - 50.1 nM) for CatK and no inhibition over the other cathepsins. This specific inhibitor harbors two novel substituents never employed in other CatK inhibitors: the trifluoromethylpyrazole and the 4-methylproline at P3 and P2 positions. These results broaden and advance the path toward new potent and selective inhibitors for CatK.
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Catepsina K , Peptidomiméticos , Prolina , Catepsina K/antagonistas & inibidores , Catepsina K/metabolismo , Peptidomiméticos/farmacologia , Peptidomiméticos/química , Peptidomiméticos/síntese química , Prolina/química , Prolina/farmacologia , Humanos , Relação Estrutura-Atividade , Estrutura Molecular , Relação Dose-Resposta a DrogaRESUMO
AIMS: This study aimed to investigate the effects of Umbelliferone (UMB) on the inflammation underlying alveolar bone resorption in mouse periodontitis. METHODS: Male Swiss mice subjected to a ligature of molars were grouped as non-treated (NT), received UMB (15, 45, or 135 mg/kg) or saline daily for 7 days, respectively, and were compared with naïve mice as control. Gingival tissues were evaluated by myeloperoxidase (MPO) activity and interleukin-1ß level by ELISA. The bone resorption was directly assessed on the region between the cement-enamel junction and the alveolar bone crest. Microscopically, histomorphometry of the furcation region, immunofluorescence for nuclear factor-kappa B (NF-ĸB), and immunohistochemistry for tartrate-resistant acid phosphatase (TRAP), and cathepsin K (CTSK) were performed. Systemically, body mass variation and leukogram were analyzed. RESULTS: Periodontitis significantly increased MPO activity, interleukin-1ß level, and NF-ĸB+ immunofluorescence, and induced severe alveolar bone and furcation resorptions, besides increased TRAP+ and CTSK+ cells compared with naïve. UMB significantly prevented the inflammation by reducing MPO activity, interleukin-1ß level, and NF-ĸB+ intensity, besides reduction of resorption of alveolar bone and furcation area, and TRAP+ and CTSK+ cells compared with the NT group. Periodontitis or UMB treatment did not affect the animals systemically. CONCLUSION: UMB improved periodontitis by reducing inflammation and bone markers.
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Perda do Osso Alveolar , Interleucina-1beta , Periodontite , Umbeliferonas , Animais , Masculino , Camundongos , Perda do Osso Alveolar/prevenção & controle , Perda do Osso Alveolar/patologia , Perda do Osso Alveolar/tratamento farmacológico , Periodontite/tratamento farmacológico , Periodontite/patologia , Umbeliferonas/uso terapêutico , Umbeliferonas/farmacologia , Osteoclastos/efeitos dos fármacos , Osteoclastos/patologia , NF-kappa B/metabolismo , Fosfatase Ácida Resistente a Tartarato/metabolismo , Peroxidase , Inflamação , Catepsina K , Ligadura , Gengiva/patologia , Gengiva/efeitos dos fármacosRESUMO
Clear cell tumors of the lung (CCTL), or "sugar tumors" of lung, are very uncommon lesions and are mostly benign perivascular epithelioid cell (PEC) tumors with no specific morphologic features. Fewer than 100 cases have been reported; the aggressive nature demonstrated in sporadic reports has rarely been described in the literature. Although the course is generally described as benign, eight reported cases showed malignant behavior. We report a case of a PEC with a malignant presentation in a young man, correlating the main characteristics of the tumor with other cases reported in the literature to better elucidate this rare presentation. We also performed a literature review of reports on benign and malignant CCTL cases, with a focus on clinical, imaging, and immunohistochemical differentiation. CCTLs are rare tumors that require histopathological and immunohistochemical confirmation; to date, criteria that can predict malignant evolution are lacking.
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Introducción: el hueso está en remodelación constante para mantener la estructura del esqueleto, tener un ciclo de resorción por los osteoclastos y formación de hueso nuevo a cargo de los osteoblastos; el hueso también es susceptible a enfermedades sistémicas, traumas, edad y trastornos genéticos que afectarán el remodelado óseo, produciendo una pérdida masiva de masa ósea regulado por hormonas, citocinas, enzimas, etcétera. El objetivo es realizar una revisión sistemática de artículos que muestren cambio o alteración al utilizar tratamientos con microvibraciones y farmacológicos sobre la catepsina K en el hueso alveolar. Material y métodos: para realizar una comparación entre la efectividad del tratamiento a base de microvibraciones y con inhibidores de la catepsina K, se realizó una revisión sistemática en nueve bases de datos (Wiley Online Library, PubMed, Google Academic, Scopus, ScienceDirect, SciELO, Medline, EBSCO y Springer Link). La población de estudio fueron ratas y ratones. Resultados: en este estudio se incluyeron 20 artículos cuya investigación se realizó en estudios clínicos. En los resultados podemos observar cómo todos los tratamientos de alguna forma mejoran el proceso de remodelado óseo. Es difícil comparar cuál de los tratamientos dentro de cada grupo es mejor que otro, debido a que los resultados expresados son cualitativos. Conclusión: acorde a los resultados expresados se opta por realizar un tratamiento con microvibraciones debido a que el uso de inhibidores de la catepsina K aún no se encuentra completamente desarrollado y no se comprenden sus consecuencias debido a su manera sistémica de actuar (AU)
Introduction: the bone is in constant remodeling to maintain the skeletal structure, having a cycle of resorption by osteoclasts and formation of new bone by osteoblasts, the bone is also susceptible to systemic diseases, trauma, age and genetic disorders that affect bone remodeling, producing a massive loss of bone mass regulated by hormones, cytokines, enzymes, etcetera. The objective is to perform a systematic review of articles that show a change or alteration when using micro-vibration and pharmacological treatments on cathepsin K in the alveolar bone. Material and methods: in order to make a comparison between the effectiveness of micro-vibration and cathepsin K inhibitor treatments, a systemic review was carried out in nine databases (Wiley Online Library, PubMed, Google Academic, Scopus, ScienceDirect, SciELO, Medline, EBSCO and Springer Link). The study population was rats and mice. Results: this study included 20 articles whose research was carried out in clinical studies. In the results we can see how all the treatments in some way improve the bone remodeling process, it is difficult to compare which treatment within each group is better than the other, because the results expressed are qualitative. Conclusion: according to the results expressed, it is decided that it is better to perform a treatment with micro vibrations because the use of cathepsin K inhibitors are not yet fully developed and their consequences are not understood due to their systemic way of acting (AU)
Assuntos
Humanos , Animais , Camundongos , Regeneração Óssea/fisiologia , Catepsina K/fisiologia , Osteoclastos/fisiologia , Técnicas de Movimentação Dentária , Bases de Dados Bibliográficas , Remodelação Óssea/fisiologiaRESUMO
Osteoclasts play a key role in the regulation of bone mass and are highly active metabolically. Here we show that a metabolic reprogramming toward the hexosamine biosynthetic pathway (HBP) is required not only for osteoclast differentiation but also to determine the bone resorption mode during physiological and pathological bone remodeling. We found that pharmacological inhibition of O-GlcNAc transferase (OGT) significantly reduced protein O-GlcNAcylation and osteoclast differentiation. Accordingly, genetic deletion of OGT also inhibited osteoclast formation and downregulated critical markers related to osteoclasts differentiation and function (NFATc1, αvintegrin, cathepsin K). Indeed, cells treated with OSMI-1, an OGT inhibitor, also reduced nuclear translocation of NFATc1. Furthermore, the addition of exogenous N-acetylglucosamine (GlcNAc) strongly increased osteoclast formation and demineralization ability. Strikingly, our data show for the first time that O-GlcNAcylation facilitates an aggressive trench resorption mode in human cells. The incubation of osteoclasts with exogenous GlcNAc increases the percentage of erosion by trench while having no effect on pit resorption mode. Through time-lapse recording, we documented that osteoclasts making trenches moving across the bone surface are sensitive to GlcNAcylation. Finally, osteoclast-specific Ogt-deficient mice show increased bone density and reduced inflammation-induced bone loss during apical periodontitis model. We show that osteoclast-specific Ogt-deficient mice are less susceptible to develop bacterial-induced periapical lesion. Consistent with this, Ogt-deleted mice showed a decreased number of tartrate-resistant acid phosphatase-positive cells lining the apical periodontitis site. In summary, here we describe a hitherto undiscovered role of the HBP/O-GlcNAcylation axis tuning resorption mode and dictating bone resorption outcome.
Assuntos
Reabsorção Óssea , Periodontite Periapical , Camundongos , Humanos , Animais , Hexosaminas/metabolismo , Vias Biossintéticas , Reabsorção Óssea/metabolismo , Osteoclastos/metabolismo , Fatores de Transcrição/metabolismoRESUMO
Abstract Objectives To evaluate the effects of matrix metalloproteinase (MMP) and cathepsin K (catK) inhibitors on resistance to dentin erosion. Methodology A total of 96 dentin specimens (3×3×2 mm) were prepared and randomly assigned into four groups (n=24): deionized water (DW); 1 µM odanacatib (ODN, catK inhibitor); 1 mM 1,10-phenanthroline (PHEN, MMP inhibitor); and 1 µM odanacatib + 1 mM 1,10-phenanthroline (COM). Each group was further divided into two subgroups for the application of treatment solutions before (PRE) and after erosive challenges (POST). All specimens were subjected to four daily erosive challenges for 5 d. For each erosive challenge, the specimens in subgroup PRE were immersed in the respective solutions before cola drinks, while the specimens in subgroup POST were immersed in the respective solutions after cola drinks (the immersion duration was 5 min in both cases). All specimens were stored in artificial saliva at 37°C between erosive challenges. The erosive dentin loss (EDL) was measured by profilometry. The residual demineralized organic matrix (DOM) of specimens was removed using type VII collagenase and evaluated by profilometry. Both the EDL and thickness of the residual DOM were statistically analyzed by two-way analysis of variance (ANOVA) and Bonferroni's test (α=0.05). The surface topography and transverse sections of the specimens were observed using SEM. MMPs and catK were immunolabeled in the eroded dentin and in situ zymography was performed to evaluate the enzyme activity. Results Significantly lower EDL was found in the groups ODN, PHEN, and COM than in the control group (all p<0.05), while no significant difference in EDL was found among the groups ODN, PHEN, and COM (all p>0.05). The application sequence showed no significant effect on the EDL of the tested groups (p=0.310). A significantly thicker DOM was observed in the group ODN than in the control group regardless of the application sequence (both p<0.05). The treatment with ODN, PHEN, and COM inhibited the gelatinolytic activity by approximately 46.32%, 58.6%, and 74.56%, respectively. Conclusions The inhibition of endogenous dentinal MMPs and catK increases the acid resistance of human dentin but without an apparent synergistic effect. The inhibition of MMPs and catK is equally effective either before or after the acid challenge.
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INTRODUCTION: Cathepsin K (CatK) is a lysosomal cysteine protease and the predominant cathepsin expressed in osteoclasts, where it degrades the bone matrix. Hence, CatK is an attractive therapeutic target related to diseases characterized by bone resorption, like osteoporosis. AREAS COVERED: This review summarizes the patent literature from 2011 to 2021 on CatK inhibitors and their potential use as new treatments for osteoporosis. The inhibitors were classified by their warheads, with the most explored nitrile-based inhibitors. Promising in vivo results have also been disclosed. EXPERT OPINION: As one of the most potent lysosomal proteins whose primary function is to mediate bone resorption, cathepsin K remains an excellent target for therapeutic intervention. Nevertheless, there is no record of any approved drug that targets CatK. The most notable cases of drug candidates targeting CatK were balicatib and odanacatib, which reached Phase II and III clinical trials, respectively, but did not enter the market. Further developments include exploring new chemical entities beyond the nitrile-based chemical space, with improved ADME and safety profiles. In addition, CatK's role in cancer immunoexpression and its involvement in the pathophysiology of osteo- and rheumatoid arthritis have raised the race to develop activity-based probes with excellent potency and selectivity.
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Reabsorção Óssea , Osteoporose , Reabsorção Óssea/tratamento farmacológico , Catepsina K/metabolismo , Humanos , Nitrilas/farmacologia , Nitrilas/uso terapêutico , Osteoporose/tratamento farmacológico , Patentes como AssuntoRESUMO
Two new series of hitherto unknown dipeptides, containing an electrophilic nitrile or a non-electrophilic 2-amino-1,3,4-oxadiazole moiety were synthesized and evaluated in vitro as Cathepsin K (Cat K) inhibitors. From 14 compounds obtained, the oxadiazole derivatives 10a, 10b, 10e, and 10g acted as enzymatic competitive inhibitors with Ki values between 2.13 and 7.33 µM. Molecular docking calculations were carried out and demonstrated that all inhibitors performed hydrogen bonds with residues from the enzyme active site, such as Asn18. The best inhibitors (10a, 10b, 10g) could also perform these bonds with Cys25, and 10a showed the most stabilizing interaction energy (-134.36 kcal mol-1) with the active cavity. For the first time, derivatives based in 2-amino-1,3,4-oxadiazole scaffolds were evaluated, and the results suggested that this core displays a remarkable potential as a building block for Cat K inhibitors.
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Catepsina K/antagonistas & inibidores , Dipeptídeos/farmacologia , Oxidiazóis/farmacologia , Sítios de Ligação , Sobrevivência Celular/efeitos dos fármacos , Simulação por Computador , Dipeptídeos/síntese química , Dipeptídeos/química , Desenho de Fármacos , Células Endoteliais da Veia Umbilical Humana , Humanos , Modelos Moleculares , Estrutura Molecular , Oxidiazóis/síntese química , Oxidiazóis/química , Ligação Proteica , Conformação Proteica , Relação Estrutura-AtividadeRESUMO
INTRODUCTION: Pycnodysostosis is a rare autosomal recessive syndrome that provides the abnormal bone metabolism that increases the susceptibility of patients to develop osteomyelitis. OBJECTIVE: This systematic review was conducted to analyze the risk factors associated with the development of complications in the jaws (fractures and osteomyelitis), as well as their clinical-pathological characteristics and therapeutic approaches in patients with pycnodysostosis. METHODS: Searches were performed in the PubMed, Web of Science, Scopus, Lilacs, and Cochrane databases. Case reports or case series that met the eligibility criteria according to the PRISMA statement were included. The full texts of 31 articles were retrieved. Twenty of these articles published between 1969 and 2018 were selected, which described 26 cases of osteomyelitis in patients with pycnodysostosis. RESULTS: The mean age of the patients was 37.84 years; the male-to-female was 1.36:1. The mandible was the most affected site (76.9%). Tooth extraction was the main risk factor for osteomyelitis (61.5%), followed by infection (26.8%) and mandibular fracture (23.0%). Antibiotic therapy alone or combined with some surgical procedure was the treatment used in most cases (80.7%). CONCLUSION: The findings of this review showed that patients with pycnodysostosis are more likely to develop osteomyelitis of the jaws after surgical procedures, especially tooth extraction which remains the main risk factor for its establishment. In addition, prophylactic antibiotic-therapy in the pre- and postoperative periods may prevent the development of osteomyelitis in pycnodysostosis.
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Osteomielite , Picnodisostose , Adulto , Feminino , Humanos , Masculino , Mandíbula , Picnodisostose/complicaçõesRESUMO
Cathepsin Z (CTSZ) is a cysteine protease responsible for the adhesion and migration of both immune and tumor cells. Due to its dual role, we hypothesized that the site of CTSZ expression could be determinant of the pro- or anti-tumorigenic effects of this enzyme. To test this hypothesis, we analyzed CTSZ expression data in healthy and tumor tissues by bioinformatics and evaluated the expression levels of CTSZ mRNA in the blood cells of prostate cancer (PCa) patients by qRT-PCR compared with healthy subjects, evaluating its diagnostic and prognostic implications for this type of cancer. Immune cells present in the blood of healthy patients overexpress CTSZ. In PCa, we found decreased CTSZ mRNA levels in blood cells, 75% lower than in healthy subjects, that diminished even more during biochemical relapse. CTSZ mRNA in the blood cells had an area under the curve for PCa diagnosis of 0.832, with a 93.3% specificity, and a positive likelihood ratio of 9.4. The site of CTSZ mRNA expression is fundamental to determine its final role as a protective determinant in PCa, such as CTSZ mRNA in the blood cells, or a malignant determinant, such as found for CTSZ expressed in high levels by different types of primary and metastatic tumors. Low CTSZ mRNA expression in the total blood is a possible PCa marker complementary to prostate-specific antigen (PSA) for biopsy decisions, with the potential to eliminate unnecessary biopsies.
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Humanos , Masculino , Neoplasias da Próstata/diagnóstico , Catepsina Z , Prognóstico , Células Sanguíneas , RNA Mensageiro , Antígeno Prostático EspecíficoRESUMO
Network theory methods and molecular dynamics (MD) simulations are accepted tools to study allosteric regulation. Indeed, dynamic networks built upon correlation analysis of MD trajectories provide detailed information about communication paths between distant sites. In this context, we aimed to understand whether the efficiency of intramolecular communication could be used to predict the allosteric potential of a given site. To this end, we performed MD simulations and network theory analyses in cathepsin K (catK), whose allosteric sites are well defined. To obtain a quantitative measure of the efficiency of communication, we designed a new protocol that enables the comparison between properties related to ensembles of communication paths obtained from different sites. Further, we applied our strategy to evaluate the allosteric potential of different catK cavities not yet considered for drug design. Our predictions of the allosteric potential based on intramolecular communication correlate well with previous catK experimental and theoretical data. We also discuss the possibility of applying our approach to other proteins from the same family.
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Catepsina K/química , Catepsina K/metabolismo , Domínios e Motivos de Interação entre Proteínas , Regulação Alostérica , Sítio Alostérico , Sítios de Ligação , Comunicação , Humanos , Modelos Moleculares , Simulação de Dinâmica Molecular , Ligação Proteica , Conformação ProteicaRESUMO
Resumen: Introducción: La picnodisostosis es una rara enfermedad secundaria en una mutación en el gen 1q21 que codifica la catepsina K, enzima implicada en el metabolismo de osteonectina, osteopontina y colágeno I. La incidencia mundial es de 1-1.7 casos por millón, sin prevalencia por género, se caracteriza clínicamente por talla baja, deformidades craneales, «cara de pájaro¼ y fragilidad ósea con tendencia a fracturas patológicas, que afectan predominantemente los huesos largos y ocasionalmente en los pedículos vertebrales. Radiológicamente es característica la presencia de osteoesclerosis con canales medulares permeables. Aunque existen numerosos reportes de casos clínicos en la literatura, pocos son los que describen familias con más de un individuo afectado y el seguimiento suele ser a corto plazo. Objetivo: Analizar la evolución clínica de los pacientes afectados. Material y métodos: Se realizó estudio retrospectivo, descriptivo, observacional de tres pacientes con diagnóstico de picnodisostosis, en el período de Julio 2006 a Marzo de 2016. Resultados: Se observaron diferentes formas de afectación de la picnodisostosis, algunas de ellas atípicas como la espondilólisis y una fractura de escápula en una paciente. Conclusiones: El presente estudio podría ser el análisis longitudinal más extenso del que se tenga registro. Conocer la variedad de manifestaciones y complicaciones presentadas permitirá al lector seleccionar el mejor método de tratamiento para cada caso.
Abstract: Introduction: Pycnodysostosis is a rare disease secondary to a mutation in gen 1q21 that codifies the cathepsin K, proteolitic enzyme implicated in the metabolism of osteonectin, osteopontin and type I colagen. Its global incidence is around 1-1.7 cases per million, without genre prevalences, it is clinically caracterized by short stature, craneal deformities, «bird's face¼ and bone fragility with pathological fractures tendency predominantly affecting long bones and occasionally vertebral pedicles. Radiologically is characterized by sclerous bones with permeable medular cannel. Despite there are numerous clinical reports on medical literature, just a litlle describe families with more than one afected member and its followship is usually short-term. Objective: To analize clinical evolution of these afected patients. Material and methods: A retrospective, descriptive, observational study was reelized in three patients with diagnosis of pycnodisostosis, between July 2006 and March 2016. Results: different affection forms of pycnodisostosis where observed, some of them, atipical, as for example spondilolisis and a escapule fracture in one patien. Conclusions: The present study could be the longest longitudinal report ever registered. By knowing the presented variety of manifestations and complications, the reader could select the best treatment method for each case.
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Humanos , Picnodisostose/complicações , Picnodisostose/diagnóstico , Fraturas Espontâneas/etiologia , Estudos Retrospectivos , Seguimentos , Catepsina K/genéticaRESUMO
INTRODUCTION: Pycnodysostosis is a rare disease secondary to a mutation in gen 1q21 that codifies the cathepsin K, proteolitic enzyme implicated in the metabolism of osteonectin, osteopontin and type I colagen. Its global incidence is around 1-1.7 cases per million, without genre prevalences, it is clinically caracterized by short stature, craneal deformities, «birds face¼ and bone fragility with pathological fractures tendency predominantly affecting long bones and occasionally vertebral pedicles. Radiologically is characterized by sclerous bones with permeable medular cannel. Despite there are numerous clinical reports on medical literature, just a litlle describe families with more than one afected member and its followship is usually short-term. OBJECTIVE: To analize clinical evolution of these afected patients. MATERIAL AND METHODS: A retrospective, descriptive, observational study was reelized in three patients with diagnosis of pycnodisostosis, between July 2006 and March 2016. RESULTS: different affection forms of pycnodisostosis where observed, some of them, atipical, as for example spondilolisis and a escapule fracture in one patien. CONCLUSIONS: The present study could be the longest longitudinal report ever registered. By knowing the presented variety of manifestations and complications, the reader could select the best treatment method for each case.
INTRODUCCIÓN: La picnodisostosis es una rara enfermedad secundaria en una mutación en el gen 1q21 que codifica la catepsina K, enzima implicada en el metabolismo de osteonectina, osteopontina y colágeno I. La incidencia mundial es de 1-1.7 casos por millón, sin prevalencia por género, se caracteriza clínicamente por talla baja, deformidades craneales, «cara de pájaro¼ y fragilidad ósea con tendencia a fracturas patológicas, que afectan predominantemente los huesos largos y ocasionalmente en los pedículos vertebrales. Radiológicamente es característica la presencia de osteoesclerosis con canales medulares permeables. Aunque existen numerosos reportes de casos clínicos en la literatura, pocos son los que describen familias con más de un individuo afectado y el seguimiento suele ser a corto plazo. OBJETIVO: Analizar la evolución clínica de los pacientes afectados. MATERIAL Y MÉTODOS: Se realizó estudio retrospectivo, descriptivo, observacional de tres pacientes con diagnóstico de picnodisostosis, en el período de Julio 2006 a Marzo de 2016. RESULTADOS: Se observaron diferentes formas de afectación de la picnodisostosis, algunas de ellas atípicas como la espondilólisis y una fractura de escápula en una paciente. CONCLUSIONES: El presente estudio podría ser el análisis longitudinal más extenso del que se tenga registro. Conocer la variedad de manifestaciones y complicaciones presentadas permitirá al lector seleccionar el mejor método de tratamiento para cada caso.
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Fraturas Espontâneas , Picnodisostose , Catepsina K/genética , Seguimentos , Fraturas Espontâneas/etiologia , Humanos , Picnodisostose/complicações , Picnodisostose/diagnóstico , Estudos RetrospectivosRESUMO
BACKGROUND: Pycnodysostosis is an autosomal recessive skeletal dysplasia, the prevalence of which is estimated to be low (1 per million). Nevertheless, in recent years we have found 27 affected individuals from 22 families in Ceará State, a region of the Brazilian Northeast, giving a local prevalence of 3 per million. This local prevalence associated with a high parental consanguinity, suggesting a possible founder effect, prompted us to perform a molecular investigation of these families to test this hypothesis. METHODS: The CTSK gene was sequenced by the Sanger method in the patients and their parents. In addition to 18 families from Ceará, this study also included 15 families from other Brazilian regions. We also investigated the origin of each family from the birthplace of the parents and/or grandparents. RESULTS: We have studied 39 patients, including 33 probands and 6 sibs, from 33 families with pycnodysostosis and identified six mutations, five previously described (c.436G>C, c.580G>A, c.721C>T, c.830C>T and c.953G>A) and one novel frameshift (c.83dupT). This frameshift variant seems to have a single origin in Ceará State, since the haplotype study using the polymorphic markers D1S2344, D1S442, D1S498 and D1S2715 suggested a common origin. Most of the mutations were found in homozygosity in the patients from Ceará (83.3 %) while in other states the mutations were found in homozygosity in half of patients. We have also shown that most of the families currently living outside of Ceará have northeastern ancestors, suggesting a dispersion of these mutations from the Brazilian Northeast. CONCLUSIONS: The high frequency of pycnodysostosis in Ceará State is the consequence of the high inbreeding in that region. Several mutations, probably introduced a long time ago in Ceará, must have spread due to consanguineous marriages and internal population migration. However, the novel mutation seems to have a single origin in Ceará, suggestive of a founder effect.
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Catepsina K/genética , Mutação , Linhagem , Polimorfismo Genético , Picnodisostose/genética , Brasil , Feminino , Efeito Fundador , Homozigoto , Humanos , MasculinoRESUMO
Las fracturas en edad pediátrica son una entidad importante para considerar. Hay enfermedades en que los huesos del niño se fracturan ante traumatismos de menor energía. La picnodisostosis es un tipo inusual de displasia cráneo-metafisaria autosómica recesiva, cuya primera manifestación clínica suele ser una fractura en hueso patológico. Se presenta a una paciente, caucásica, de 9 años de edad, con diagnóstico de picnodisostosis, que ingresó al hospital por fractura del fémur derecho, por un mecanismo de baja energía. Los estudios radiográficos mostraron fracturas del fémur bilateral, fractura proximal de la tibia izquierda y consolidación viciosa en antecurvatum. Esta rara enfermedad se diagnostica a edades tempranas por talla baja, por fracturas repetidas o por traumas de baja energía. Las opciones terapéuticas son limitadas, y no se ha desarrollado una cura definitiva. Es importante, ante un paciente pediátrico con rasgos dismórficos faciales y fracturas en hueso patológico, sospechar displasias óseas, tales como la picnodisostosis y sus diagnósticos diferenciales.
Fractures are an important entity to consider in pediatric patients. There are certain diseases in which bones fracture with a minimal trauma. Pycnodysostosis is an autosomal recessive unusual type of cráneo metaphyseal dysplasia, that presents frequently as fracture in a pathological bone. A 9 year old caucasian female, diagnosed with pycnodysostosis, was admitted with a right femur fracture as a result of a low energy trauma. Radiographic studies showed bilateral femur fractures, proximal fracture and non-union in antecurvatum of the left tibia. Pycnodysostosis is a rare disease, generally diagnosed at an early age by growth restriction, frequent fractures or fractures with low energy trauma. Therapy alternatives are limited, and no permanent cure has been developed. If a patient has dysmorphic facial features and fractures in a pathological bone, it is important to suspect bone dysplasia, such as pycnodysostosis and its differential diagnoses.
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Humanos , Feminino , Criança , Traumatismo Múltiplo/etiologia , Fraturas Ósseas/etiologia , Picnodisostose/complicaçõesRESUMO
Fractures are an important entity to consider in pediatric patients. There are certain diseases in which bones fracture with a minimal trauma. Pycnodysostosis is an autosomal recessive unusual type of cráneo metaphyseal dysplasia, that presents frequently as fracture in a pathological bone. A 9 year old caucasian female, diagnosed with pycnodysostosis, was admitted with a right femur fracture as a result of a low energy trauma. Radiographic studies showed bilateral femur fractures, proximal fracture and non-union in antecurvatum of the left tibia. Pycnodysostosis is a rare disease, generally diagnosed at an early age by growth restriction, frequent fractures or fractures with low energy trauma. Therapy alternatives are limited, and no permanent cure has been developed. If a patient has dysmorphic facial features and fractures in a pathological bone, it is important to suspect bone dysplasia, such as pycnodysostosis and its differential diagnoses.
Las fracturas en edad pediátrica son una entidad importante para considerar. Hay enfermedades en que los huesos del niño se fracturan ante traumatismos de menor energía. La picnodisostosis es un tipo inusual de displasia cráneo-metafisaria autosómica recesiva, cuya primera manifestación clínica suele ser una fractura en hueso patológico. Se presenta a una paciente, caucásica, de 9 años de edad, con diagnóstico de picnodisostosis, que ingresó al hospital por fractura del fémur derecho, por un mecanismo de baja energía. Los estudios radiográficos mostraron fracturas del fémur bilateral, fractura proximal de la tibia izquierda y consolidación viciosa en antecurvatum. Esta rara enfermedad se diagnostica a edades tempranas por talla baja, por fracturas repetidas o por traumas de baja energía. Las opciones terapéuticas son limitadas, y no se ha desarrollado una cura definitiva. Es importante, ante un paciente pediátrico con rasgos dismórficos faciales y fracturas en hueso patológico, sospechar displasias óseas, tales como la picnodisostosis y sus diagnósticos diferenciales.
Assuntos
Fraturas Ósseas/etiologia , Traumatismo Múltiplo/etiologia , Picnodisostose/complicações , Criança , Feminino , HumanosRESUMO
The NOD-like receptors are cytoplasmic proteins that sense microbial by-products released by invasive bacteria. Although NOD1 and NOD2 are functionally expressed in cells from oral tissues and play a role triggering immune responses, the role of NOD2 receptor in the bone resorption and in the modulation of osteoclastogenesis is still unclear. We show that in an experimental model of periodontitis with Porphyromonas gingivalis W83, NOD2(-/-) mice showed lower bone resorption when compared to wild type. Quantitative polymerase chain reaction analysis revealed that wild-type infected mice showed an elevated RANKL/OPG ratio when compared to NOD2(-/-) infected mice. Moreover, the expression of 2 osteoclast activity markers-cathepsin K and matrix metalloproteinase 9-was significantly lower in gingival tissue from NOD2(-/-) infected mice compared to WT infected ones. The in vitro study reported an increase in the expression of the NOD2 receptor 24 hr after stimulation of hematopoietic bone marrow cells with M-CSF and RANKL. We also evaluated the effect of direct activation of NOD2 receptor on osteoclastogenesis, by the activation of this receptor in preosteoclasts culture, with different concentrations of muramyl dipeptide. The results show no difference in the number of TRAP-positive cells. Although it did not alter the osteoclasts differentiation, the activation of NOD2 receptor led to a significant increase of cathepsin K expression. We confirm that this enzyme was active, since the osteoclasts resorption capacity was enhanced by muramyl dipeptide stimulation, evaluated in osteoassay plate. These results show that the lack of NOD2 receptor impairs the bone resorption, suggesting that NOD2 receptor could contribute to the progression of bone resorption in experimental model of periodontitis. The stimulation of NOD2 by its agonist, muramyl dipeptide, did not affect osteoclastogenesis, but it does favor the bone resorption capacity identified by increased osteoclast activity.
Assuntos
Perda do Osso Alveolar/microbiologia , Proteína Adaptadora de Sinalização NOD2/fisiologia , Porphyromonas gingivalis/fisiologia , Acetilmuramil-Alanil-Isoglutamina/farmacologia , Adjuvantes Imunológicos/farmacologia , Perda do Osso Alveolar/patologia , Animais , Catepsina K/análise , Contagem de Células , Diferenciação Celular/efeitos dos fármacos , Células Cultivadas , Modelos Animais de Doenças , Relação Dose-Resposta a Droga , Gengiva/química , Células-Tronco Hematopoéticas/efeitos dos fármacos , Fator Estimulador de Colônias de Macrófagos/farmacologia , Masculino , Metaloproteinase 9 da Matriz/análise , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteína Adaptadora de Sinalização NOD2/agonistas , Osteoclastos/efeitos dos fármacos , Osteoclastos/patologia , Osteoprotegerina/análise , Ligante RANK/análise , Ligante RANK/farmacologia , Fatores de TempoRESUMO
Pyknodysostosis is a rare autosomal recessive skeletal dysplasia characterized by short stature, deformity of the skull, osteosclerosis, hypoplasia of the clavicle, and bone fragility. Radiographs show increased bone density, osteosclerosis, and acroosteolysis of the terminal phalanges. The pycnodysostosis gene is located on chromosome 1q21 and encodes an enzyme called Cathepsin K. Cathepsin K is a cysteine protease lysosomal protein associated with the degradation of bone and cartilage. In the current study, the authors described the clinical, radiological and molecular features of a group of six Mexican patients, including two familial and two sporadic cases, with Pyknodysostosis. One of the patients presented hypoacusia, an unusual finding in this disease.
RESUMO
Human bones are in a continuous process of remodeling that ensures renovation and maintenance of the skeletal mass. Bone remodeling has two phases that are normally coupled and balanced: bone resorption mediated by osteoclasts and bone formation mediated by osteoblasts. An increase in bone resorption over bone formation results in a progressive loss of bone mass and impairment of bone microarchitecture leading to osteoporosis and its associated fractures. Recent advances in the understanding of the molecular and cellular mechanisms involved in the remodeling process have allowed the development of new targets for osteoporosis treatment. Cathepsin K, a cysteine protease, is found in osteoclasts along the bone resorption surfaces and very efficiently degrades type I collagen, the major component of the organic bone matrix. Inhibition of cathepsin K reduces bone resorption but does not impair bone formation particularly at cortical sites. Odanacatib, a potent and highly selective cathepsin K inhibitor, showed prevention of bone loss without reduction of bone formation in preclinical and clinical trials (phase I and II). Odanacatib is currently in a phase III fracture outcome international trial for the treatment of postmenopausal osteoporosis.