RESUMEN
OBJECTIVE: We aimed to understand the role of the tyrosine phosphatase PTPN14-which in cancer cells modulates the Hippo pathway by retaining YAP in the cytosol-in fibroblast-like synoviocytes (FLS) from patients with rheumatoid arthritis (RA). METHODS: Gene/protein expression levels were measured by quantitative PCR and/or Western blotting. Gene knockdown in RA FLS was achieved using antisense oligonucleotides. The interaction between PTPN14 and YAP was assessed by immunoprecipitation. The cellular localisation of YAP and SMAD3 was examined via immunofluorescence. SMAD reporter studies were carried out in HEK293T cells. The RA FLS/cartilage coimplantation and passive K/BxN models were used to examine the role of YAP in arthritis. RESULTS: RA FLS displayed overexpression of PTPN14 when compared with FLS from patients with osteoarthritis (OA). PTPN14 knockdown in RA FLS impaired TGFß-dependent expression of MMP13 and potentiation of TNF signalling. In RA FLS, PTPN14 formed a complex with YAP. Expression of PTPN14 or nuclear YAP-but not of a non-YAP-interacting PTPN14 mutant-enhanced SMAD reporter activity. YAP promoted TGFß-dependent SMAD3 nuclear localisation in RA FLS. Differences in epigenetic marks within Hippo pathway genes, including YAP, were found between RA FLS and OA FLS. Inhibition of YAP reduced RA FLS pathogenic behaviour and ameliorated arthritis severity. CONCLUSION: In RA FLS, PTPN14 and YAP promote nuclear localisation of SMAD3. YAP enhances a range of RA FLS pathogenic behaviours which, together with epigenetic evidence, points to the Hippo pathway as an important regulator of RA FLS behaviour.
Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/fisiología , Proteínas Tirosina Fosfatasas no Receptoras/fisiología , Transducción de Señal/fisiología , Sinoviocitos/metabolismo , Factores de Transcripción/fisiología , Factor de Crecimiento Transformador beta/fisiología , Animales , Artritis Reumatoide/metabolismo , Proteínas de Ciclo Celular/fisiología , Humanos , Ratones , Proteínas Señalizadoras YAPRESUMEN
Osteoporosis is a skeletal disease characterized by loss of bone strength and increased risk of fractures. Even though fracture prevalence is higher in women, fractures also constitute a significant public health issue in older men. Men are screened less and more frequently undertreated than female patients. It is the goal of this review, to summarize updated information about the current understanding of pathophysiology and clinical aspects of diagnosis and treatment of osteoporosis in men.