Integrin α1ß1 differentially regulates cytokine-mediated responses in chondrocytes.

OBJECTIVE: To elucidate the role of integrin α1ß1 in chondrocyte responses to inflammatory interleukin-1α (IL-1) and anabolic transforming growth factor-ß1 (TGF-ß1) in the knee. METHODS: Intracellular calcium transient responses to IL-1 and TGF-ß1 were measured in wild type and integrin α1-null chondrocytes using real time ex vivo confocal microscopy, and immunohistochemistry was performed to analyze TGF-ß1-mediated activation of Smad2/3 in tibial and femoral chondrocytes. RESULTS: Loss of integrin α1ß1 reduces intracellular calcium transient response to IL-1, while it enhances chondrocyte responses to TGF-ß1 as measured by intracellular calcium transients and activation of downstream Smad2/3. CONCLUSIONS: Integrin α1ß1 plays a vital role in mediating chondrocyte responses to two contrasting factors that are critical players in the onset and progression of osteoarthritis - inflammatory IL-1 and anabolic TGF-ß. Further investigation into the molecular mechanisms by which integrin α1ß1 mediates these responses will be an important next step in understanding the influence of increased expression of integrin α1ß1 during the early stages of osteoarthritis on disease progression.

Pkd1-targeted mutation reveals a role for the Wolffian duct in autosomal dominant polycystic kidney disease.

Several life-threatening diseases of the kidney have their origins in mutational events that occur during embryonic development. In this study, we investigate the role of the Wolffian duct (WD), the earliest embryonic epithelial progenitor of renal tubules, in the etiology of autosomal dominant polycystic kidney disease (ADPKD). ADPKD is associated with a germline mutation of one of the two Pkd1 alleles. For the disease to occur, a second event that disrupts the expression of the other inherited Pkd1 allele must occur. We postulated that this secondary event can occur in the pronephric WD. Using Cre-Lox recombination, mice with WD-specific deletion of one or both Pkd1 alleles were generated. Homozygous Pkd1-targeted deletion in WD-derived tissues resulted in mice with large cystic kidneys and serologic evidence of renal failure. In contrast, heterozygous deletion of Pkd1 in the WD led to kidneys that were phenotypically indistinguishable from control in the early postnatal period. High-throughput sequencing, however, revealed underlying gene and microRNA (miRNA) changes in these heterozygous mutant kidneys that suggest a strong predisposition toward developing ADPKD. Bioinformatic analysis of this data demonstrated an upregulation of several miRNAs that have been previously associated with PKD; pathway analysis further demonstrated that the differentially expressed genes in the heterozygous mutant kidneys were overrepresented in signaling pathways associated with maintenance and function of the renal tubular epithelium. These results suggest that the WD may be an early epithelial target for the genetic or molecular signals that can lead to cyst formation in ADPKD.

Mental health services for Chinese in a community health center.

Serious mental health problems exist within the Chinese population of the United States. This article describes one center's attempt to meet the psychiatric needs of both nonpsychotic and psychotic Chinese patients through bilingual, culturally relevant treatments.