Tumor necrosis factor-alpha (TNF-alpha) is a skeletal catabolic agent that stimulates osteoclastogenesis and inhibits osteoblast function. Although TNF-alpha inhibits the mineralization of osteoblasts, the effect of TNF-alpha on mesenchymal stem cells (MSC) is not clear. In this study, we determined the effect of TNF-alpha on osteogenic differentiation of stromal cells derived from human adipose tissue (hADSC) and the role of NF-kappaB activation on TNF-alpha activity. TNF-alpha treatment dose-dependently increased osteogenic differentiation over the first 3 days of treatment. TNF-alpha activated ERK and increased NF-kappaB promoter activity. PDTC, an NF-kappaB inhibitor, blocked the osteogenic differentiation induced by TNF-alpha and TLR-ligands, but U102, an ERK inhibitor, did not. Overexpression of miR-146a induced the inhibition of IRAK1 expression and inhibited basal and TNF-alpha- and TLR ligand-induced osteogenic differentiation. TNF-alpha and TLR ligands increased the expression of transcriptional coactivator with PDZ-binding motif (TAZ), which was inhibited by the addition of PDTC. A ChIP assay showed that p65 was bound to the TAZ promoter. TNF-alpha also increased osteogenic differentiation of human gastroepiploic artery smooth muscle cells. Our data indicate that TNF-alpha enhances osteogenic differentiation of hADSC via the activation of NF-kappaB and a subsequent increase of TAZ expression.

These findings collectively suggest that WNT5A may be a key gene that induces CRPC in the bone niche by recruiting and regulating macrophages through CCL2 and BMP6, respectively.

Background:Identifying risk factors that contribute to shoulder and elbow pain within youth baseball players is important for improving injury prevention and rehabilitation strategies.Hypothesis:Differences will exist between youth baseball players with and without a history of upper extremity pain on measures related to growth, shoulder performance, and baseball exposure.Study Design:Case-control study; Level of evidence, 3.Methods:A total of 84 youth baseball players were divided into 2 groups based on self-reported history of throwing-related arm pain. Group differences for growth-related, shoulder performance, and baseball exposure variables were analyzed by use of parametric and nonparametric tests, as appropriate. Multivariate logistic regression was used to assess variables most predictive of pain.Results:The group of athletes with pain (n = 16) were taller and heavier, played more baseball per year, and had greater pitching velocity. Athletes with pain also had greater loss of internal rotation range of motion and greater side-to-side asymmetry in humeral retrotorsion (HRT), attributable to lower degrees of HRT within the nondominant humerus. Multivariate analysis revealed that player height was most predictive of pain, with a 1-inch increase in height resulting in a 77% increased risk of pain.Conclusion:Vertical growth that accompanies adolescence increases the risk of experiencing throwing-related pain in youth baseball players. Players who are taller, particularly those with faster pitching velocities, are at the greatest risk for developing pain and should be more carefully monitored for resultant injury. The degree of nondominant HRT may have a relationship to the development of pain, but further research is required to better understand the implications of this observation.

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In this study, we determined the effect of TNF-α on hBMSCs proliferation as well as the role of IL-1 receptor-associated kinase 1 (IRAK1) on TNF-α signaling. Western blot analysis revealed that TNF-α treatment increased the phosphorylation of IRAK1 in hBMSCs. The downregulation of IRAK1 inhibited TNF-α-induced NF-ĸB activation and COX-2 expression. TNF-α treatment increased hBMSCs proliferation in a dose-dependent manner and increased ERK, JNK, and NF-ĸB activity. U0126, an ERK inhibitor, decreased hBMSCs proliferation and significantly blocked TNF-α -induced hBMSCs proliferation. In cells with IRAK1 or TRADD downregulation, the U0126 treatment inhibited hBMSCs proliferation and significantly suppressed TNF-α-induced hBMSCs proliferation. The downregulation of IRAK1 or TRADD inhibited TNF-α-induced ERK and JNK activation, and hBMSCs proliferation. Inhibition of NF-ĸB by decoy oligonucleotides reduced the TNF-α-induced hBMSCs proliferation. Immunoprecipitation analysis showed that IRAK1 does not physically interact with TNF receptor 1 (TNFR1) even in the presence of TNF-α. Suppression of IRAK1 binding protein (IRAK1BP1) inhibited TNF-α-induced increase of the proliferation and ERK1 phosphorylation of hBMSCs in the presence of TNF-α. Our data indicate that TNF-α modulates hBMSCs proliferation through ERK signaling pathways, and that IRAK1 plays an important role in TNF-α-induced NF-ĸB activation in hBMSCs.