Osteoporosis is defined as an osteometabolic disease characterized by the reduction of bone mineral density (BMD) and micro-architectural deterioration, leading to enhanced bone fragility and increased susceptibility to fractures. Chronic inflammation affecting bone resorption and/or bone formation is an important mechanism in the hystopathology of osteoporosis. In this regard, several inflammatory markers are associated in special, tumor necrosis factor alpha (TNFα). Recent evidence from the literature pointed out that other members of the TNF superfamily, the tumor necrosis factor TNF-like weak inducer of apoptosis (TWEAK), in its soluble bioactive form (sTWEAK), has been related with diverse endocrine metabolic disarrangements such as diabetes mellitus or metabolic syndrome. Thus, we hypothesized a possible association between sTWEAK plasma levels and bone fractures and diabetes mellitus in post menopausal women. This was a cross sectional study nested in a cohort of 1057 post menopausal women outpatients attending the UBS, Unidades Básicas de Saúde, of Santa Maria. We used data from 52 individuals recruited who reported major bone fractures. For the control group, we aleatory recruited 110 individuals without the history of major bone fractures. All subjects in this study proceeded to a standard questionnaire about clinical data and were submitted to anthropometry evaluation. Blood samples were obtained for the biochemical profile consisting in fast glucose, total cholesterol, TG, HDL, LDL, creatinine, albumin, calcium and phosphorus in serum. sTWEAK concentration was established by ELISA. Assimetric variables were logN transformed. Student T test or Mann-Whitney test were used to comparison of data between two groups. For statistical analysis that form more than two groups were employed ANOVA or Chi quadrate and Fisher s test. An statistical significant reduction (p=0.002) of sTWEAK (log transformed) was observed in diabetes mellitus (DM) subjects in comparison to non-diabetics. There was no differences in the plasma levels of sTWEAK when the history of major bone fractures was analysed. Even when stratified for DM and fractures, Ln sTWEAK remained consistently reduced in the group of individuals with DM without fractures against non-diabetics no-fractures women (p <0.01). Findings from this study indicated that plasma levels of sTWEAK was not related with bone fragility in post menopausal women population. Nevertheless, low plasma levels of this biomarker were associated with diabetes mellitus, as previously described in the literature. / A osteoporose é um transtorno osteometabólico caracterizado pela diminuição da densidade mineral óssea (DMO) e deterioração de sua microarquitetura com o consequente aumento da fragilidade do osso e suscetibilidade à fraturas. A fisiopatologia dessa doença tem a inflamação crônica como importante mecanismo no aumento da reabsorção e redução da formação óssea. Entre os marcadores inflamatórios associados à osteoporose destacam-se aqueles do grupo dos fatores de necrose tumoral, em particular, o fator de necrose tumoral alfa (TNFα). Evidências recentes da literatura observaram que um outro membro da mesma família, o TNFlike weak inducer of apoptosis (TWEAK), em sua forma solúvel (sTWEAK), foi relacionado com a presença de outros distúrbios endócrino metabólicos, tais como diabetes mellitus (DM) e síndrome metabólica. Com base nisso, testamos a hipótese de associação entre sTWEAK e fraturas ósseas maiores, e também DM, em mulheres na pós menopausa. Este é um estudo transversal que partiu de uma coorte de 1057 pacientes na pós menopausa que consultam nas Unidades Básicas de Saúde da cidade de Santa Maria-RS. Foram recrutadas 52 pacientes com histórico de fraturas ósseas maiores e, para o grupo controle, escolhidas aleatoriamente 110 pacientes sem história de fraturas ósseas. Todos os indivíduos do estudo responderam a um questionário padronizado sobre a sua história clínica além de serem submetidos a avaliação antropométrica e exames bioquímicos (glicose de jejum, colesterol total, triglicerídeos, HDL, LDL, creatinina, albumina, cálcio e fósforo). Os níveis plasmáticos de sTWEAK foram avaliados pelo método de ELISA. As variáveis com distribuição assimétrica foram submetidas à transformação para o seu logaritmo natural e então comparadas. Para a análise estatística entre dois grupos foi feita a utilização dos testes T de Student ou Mann-Whitney. Para mais de dois grupos foram empregados ANOVA ou os testes de Chi Quadrado ou Fisher. Foi observada redução significativa (p=0.002) dos valores do sTWEAK (transformado para logN) nos indivíduos com DM em comparação com os sem DM. Não houveram diferenças quando analisado somente o histórico de fraturas. Estratificando a população em subgrupos de acordo com o critério de existência de fratura reportada ou de diagnóstico de DM, permaneceu somente a diferença entre os grupos com DM sem fratura e sem DM sem fratura (p<0.01). Os achados indicam que na população de mulheres na pós menopausa com e sem história de fraturas ósseas maiores, os níveis plasmáticos de sTWEAK não tem associação com a fragilidade óssea. Entretanto, níveis baixos deste biomarcador estão associados com o diagnóstico de DM, como reportado na literatura.

The NF-κB family of transcription factors can be activated through canonical (classical) or non-canonical (alternative) signalling pathways, which are regulated by the redundant ubiquitin ligases, cellular inhibitor of apoptosis 1 and 2 (cIAP1 and cIAP2). While the canonical NF-κB pathway is needed for myoblast proliferation, it is inactivated during myoblast differentiation. However, the non-canonical NF-κB pathway is a major factor in promoting myoblast fusion, which is crucial to the processes of myogenesis and muscle repair. Ablation of cIAP1 levels through a chemical antagonist such as a SMAC- mimetic compound (SMC) activates non-canonical signalling to enhance myogenesis. The cytokine TNF-like weak inducer of apoptosis (TWEAK) has also been shown to activate primarily the alternative NF-κB pathway when signalling through its receptor Fn14. Here I show that alternative NF-κB signalling activity, stimulated by the addition of TWEAK or loss of cIAP1, can promote myogenesis. I also demonstrate that TWEAK is an endogenous myokine produced by myoblasts to promote their own differentiation, and suggest that targeting the alternative NF-κB pathway, with SMAC-mimetics or recombinant TWEAK for example, would be of therapeutic value in the repair and regeneration of muscle for various myopathies.