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Doctoral Thesis
DOI
10.11606/T.5.2018.tde-05122018-115114
Document
Author
Full name
Valéria de Falco Caparbo
E-mail
Institute/School/College
Knowledge Area
Date of Defense
Published
São Paulo, 2018
Supervisor
Committee
Pereira, Rosa Maria Rodrigues (President)
Borba Neto, Eduardo Ferreira
Domiciano, Diogo Souza
Machado, Luana Gerheim
Title in Portuguese
Avaliação do papel da osteoclastogênese e ativação dos osteoclastos em pacientes com espondilite anquilosante
Keywords in Portuguese
Apoptose
Colágeno tipo I
Espondilite anquilosante
Ligante RANK
Marcadores biológicos
Osteoclastos
Osteoprotegerina
Abstract in Portuguese
Objetivo: investigar a capacidade osteoclastogênica de células mononucleares do sangue periférico (PBMCs) de pacientes do sexo masculino com espondilite anquilosante (EA), comparando com indivíduos saudáveis e determinar a relação da osteoclastogênese com parâmetros clínicos e laboratoriais. Métodos: células mononucleares do sangue periférico de 85 pacientes com espondilite anquilosante e 59 controles saudáveis (CT) foram marcadas para avaliar a presença de células CD16 positivas (precursores de osteoclastos). As PBMCs foram mantidas, in vitro, por 21 dias para indução da diferenciação em osteoclastos e avaliação da apoptose destas células. Os níveis séricos do ligante do receptor ativador de fator nuclear kB (RANKL), osteoprotegerina (OPG), telopeptídeo C-terminal do colágeno tipo I (CTX) e propeptídeo Nterminal do procolágeno tipo I (P1NP) foram também avaliados. Resultados: PBMCs de pacientes com EA apresentaram menor porcentagem de células CD16 positivas (25,06 ± 8,59 vs. 28,59 ± 10,20%; p = 0,026) e originaram menor número de osteoclastos comparados aos controles saudáveis (647,7 ± 669,4 vs. 764,4 ± 561,9 OC/poço; p = 0,014). A porcentagem de osteoclastos em apoptose foi menos frequente nos pacientes com EA versus CT (31,8 ± 32,5 vs. 44,5 ± 34,3%; p = 0,007). Menores relações RANKL/OPG e CTX/P1NP foram observadas nos pacientes com EA em relação aos CT (0,05 ± 0,03 vs. 0,07 ± 0,07; p = 0,046 e 0,008 ± 0,003 vs. 0,010 ± 0,003; p < 0,001, respectivamente). Pacientes com EA em uso de terapia de anti-inflamatório não-hormonal (AINH) não apresentaram diferença associada ao número de osteoclastos gerados e à porcentagem de células CD16 positivas comparados aos CT (p > 0,05). Entretanto, pacientes com EA em uso de terapia com inibidor de TNFalfa (iTNFalfa) demonstraram menor número de osteoclastos gerados comparados aos indivíduos saudáveis (582,51 ± 717,56 vs. 764,43 ± 561,9 OC/poço; p = 0,047). Observou-se uma correlação negativa entre número de osteoclastos gerados a partir de PBMC de pacientes com EA e duração de doença (R = -0,220, p = 0,043). Conclusões: os presentes resultados demonstraram que monócitos de pacientes com EA apresentam uma menor capacidade em gerar osteoclastos comparados a indivíduos saudáveis, e que a osteoclastogênese esteve correlacionada negativamente à duração de doença. Estes dados sugerem que os osteoclastos possuem um papel importante na fisiopatologia da doença óssea nos pacientes com EA
Title in English
Evaluation of the role of osteoclastogenesis and activation of osteoclasts in patients with ankylosing spondylitis
Keywords in English
Ankylosing spondylitis
Apoptosis
Biological markers
Osteoclasts
Osteoprotegerin, RANK ligand
Type I collagen
Abstract in English
Objective: the aim of this study was to investigate if the osteoclastogenic capacity of PBMCs is different in AS patients compared to controls and the relationship between osteoclastogenesis and clinical/laboratory parameters. Methods: PBMCs from 85 male ankylosing spondylitis (AS) patients and 59 controls were tested for CD16+ cells and induced to differentiate into osteoclasts over 3 weeks in vitro. Serum levels of RANKL, osteoprotegerin (OPG), C-terminal telopeptide of type I collagen (CTX) and N-terminal propeptide of type 1 collagen (P1NP) were also evaluated. Results: PBMCs from AS patients had fewer CD16+ cells (25.06 ± 8.59 vs. 28.59 ± 10.20%; p = 0.026) and produced fewer osteoclasts (647.7 ± 669.4 vs. 764.4 ± 561.9 OC/well; p = 0.014) compared to controls. Apoptosis occurred less frequently in osteoclasts obtained from AS patients than in osteoclasts from the controls (31.8 ± 32.5 vs. 44.5 ± 34.3%; p = 0.007). A lower RANKL/OPG and CTX/P1NP were observed in AS patients compared to controls (0.05 ± 0.03 vs. 0.07 ± 0.07; p = 0.046 e 0.008 ± 0.003 vs. 0.010 ± 0.003; p < 0.001, respectively). AS patients taking NSAIDs presented no difference regarding the number of OCs produced and the percentage of CD16+ cells compared to controls (p > 0.05). However, patients taking TNFalpha inhibitors (TNFi) presented lower OC numbers than controls (582.51 ± 717.56 vs. 764.43 ± 561.9 OC/well; p = 0.047). A negative correlation was demonstrated between the number of osteoclasts generated from PBMCs of AS patients and disease duration (R = -0.220, p = 0.043). Conclusion: monocytes from male AS patients display a lower capacity to generate osteoclasts in vitro compared to cells from controls. Osteoclastogenesis was negatively correlated with disease duration. This finding supports the idea that osteoclasts play a role in the physiopathology of bone disease in AS patients
 
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Publishing Date
2018-12-10
 
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