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Osteoporosis results from an imbalance in skeletal remodeling that favors bone resorption over bone formation. Bone matrix is degraded by osteoclasts, which differentiate from myeloid precursors in response to the cytokine RANKL. To gain insight into the transcriptional regulation of bone resorption during growth and disease, we generated a conditional knockout of the transcription factor nuclear factor of activated T cells c1 (Nfatc1). Deletion of Nfatc1 in young mice resulted in osteopetrosis and inhibition of osteoclastogenesis in vivo and in vitro. Transcriptional profiling revealed NFATc1 as a master regulator of the osteoclast transcriptome, promoting the expression of numerous genes needed for bone resorption. In addition, NFATc1 directly repressed osteoclast progenitor expression of osteoprotegerin, a decoy receptor for RANKL previously thought to be an osteoblast-derived inhibitor of bone resorption. "Cherubism mice", which carry a gain-of-function mutation in SH3-domain binding protein 2 (Sh3bp2), develop osteoporosis and widespread inflammation dependent on the proinflammatory cytokine, TNF-[alpha]. Interestingly, deletion of Nfatc1 protected cherubism mice from systemic bone loss but did not inhibit inflammation. Taken together, our study demonstrates that NFATc1 is required for remodeling of the growing and adult skeleton and suggests that NFATc1 may be an effective therapeutic target for osteoporosis associated with inflammatory states., Introduction Osteoporosis, the most common pathologic condition resulting from excessive bone destruction, afflicts 10 million Americans over the age of 50 and results in 1.5 million fractures annually (1), (2). [...]

The transmembrane, dystrophin-associated protein varGamma-sarcoglycan is expressed in skeletal and cardiac muscle. Mice lacking varGamma-sarcoglycan exhibited distinct dystrophic muscle changes early in life, and loss of varGamma-sarcoglycan led to secondary reduction of beta- and varDelta, with a partial retention of alpha- and varEpsilon-sarcoglycan. Sarcoglycan loss was found to be sufficient and that dystrophin loss was not required to cause membrane defects and apoptosis.

The influence of eosinophil major basic protein (MBP) on prostaglandin (PG) secretion was studied in guinea pig tracheal epithelial (GPTE) cells. It was observed that the cells used in the study had cytokeratin, as revealed by staining to antikeratin antibody. These cells were also identified to be epithelial due to the presence of cilia and desmosomes. It was concluded that MBP induces secretion of PGE2 and PGF2 alpha from GPTE cells in culture. It also increases the secretion of PGE2 and PGF2 alpha to bradykinin.

Sucrose nonfermenting-related kinase (SNRK) is a member of the AMPK-related kinase family, and its physiological role in adipose energy homeostasis and inflammation remains unknown. We previously reported that SNRK is ubiquitously and abundantly expressed in both white adipose tissue (WAT) and brown adipose tissue (BAT), but SNRK expression diminishes in adipose tissue in obesity. In this study we report novel experimental findings from both animal models and human genetics. SNRK is essential for survival; SNRK globally deficient pups die within 24 h after birth. Heterozygous mice are characterized by inflamed WAT and less BAT. Adipocyte-specific ablation of SNRK causes inflammation in WAT, ectopic lipid deposition in liver and muscle, and impaired adaptive thermogenesis in BAT. These metabolic disorders subsequently lead to decreased energy expenditure, higher body weight, and insulin resistance. We further confirm the significant association of common variants of the SNRK gene with obesity risk in humans. Through applying a phosphoproteomic approach, we identified eukaryotic elongation factor 1δ and histone deacetylase 1/2 as potential SNRK substrates. Taking these data together, we conclude that SNRK represses WAT inflammation and is essential to maintain BAT thermogenesis, making it a novel therapeutic target for treating obesity and associated metabolic disorders. [ABSTRACT FROM AUTHOR]