We investigated the role of periostin, an extracellular matrix protein, in the pathophysiology of osteoarthritis (OA). In OA, dysregulated gene expression and phenotypic changes in articular chondrocytes culminate in progressive loss of cartilage from the joint surface. The molecular mechanisms underlying this process are poorly understood. We examined periostin expression by immunohistochemical analysis of lesional and nonlesional cartilage from human and rodent OA knee cartilage. In addition, we used small interfering (si)RNA and adenovirus transduction of chondrocytes to knock down and upregulate periostin levels, respectively, and analyzed its effect on matrix metalloproteinase (MMP)-13, a disintegrin and MMP with thrombospondin motifs (ADAMTS)-4, and type II collagen expression. We found high periostin levels in human and rodent OA cartilage. Periostin increased MMP-13 expression dose [1-10 mg/ml (EC 50 0.5-1 mg/ml)] and time (24-72 h) dependently, significantly enhanced expression of ADAMTS4 mRNA, and promoted cartilage degeneration through collagen and proteoglycan degradation. Periostin induction of MMP-13 expression was inhibited by CCT031374 hydrobromide, an inhibitor of the canonical Wnt/b-catenin signaling pathway. In addition, siRNA-mediated knockdown of endogenous periostin blocked constitutive MMP-13 expression. These findings implicate periostin as a catabolic protein that promotes cartilage degeneration in OA by upregulating MMP-13 through canonical Wnt signaling.-Attur, M

Mesenchymal stem cells (MSCs) have therapeutic potential in various diseases, including myocardial infarction. Recently, the importance of the therapeutic effects of secreted factors from MSCs is increasing, but their identification has not progressed. In this study, we uncover the secreted protein profiles of MSCs derived from bone marrow, adipose tissue and dental pulp. Shotgun proteome analysis of conditioned MSC media by mass spectrometry identified 1533 proteins totally and 124 secreted proteins commonly produced among all three MSCs. The commonly secreted factors include already well-known factors whose functions are linked to MSCs' biological effects, such as CTGF, SERPINE1, TGFB1, DKK3 and MYDGF, and also include newly identified factors whose roles are not well investigated, for example AIMP1, CLEC11A, GAS6, HDGF, INHBA, and PCSK5. Computational biological pathway analysis revealed that these common factors strongly relate to tissue regeneration pathways such as angiogenesis, migration, and inflammatory response. Further analysis showed enrichment of ossification, sprouting, and organ survival factors, suggesting connection to the functions closely related to MSCs' therapeutic effects. This list of commonly secreted proteins could provide a reliable resource of biological factors which explain various effects of MSCs and would be useful for identifying new therapeutic factors produced from MSCs.

Our findings demonstrate that upregulated expression of DIO2 in OA patient cartilage might be responsible for OA pathogenesis by enhancing the chondrocyte hypertrophy and inflammatory response.

Background: Mast cells (MCs) play pivotal roles in allergy and innate immunity and consist of heterogenous subclasses. However, the molecular basis determining the different characteristics of these multiple MC subclasses remains unclear.

Hereditary hemorrhagic telangiectasia is characterized by the formation of abnormal vascular networks and caused by the mutation of genes involved in BMP9 signaling. It is also known that the interaction between endothelial cells (ECs) and mural cells (MCs) is critical to maintain vessel integrity. However, it has not yet fully been uncovered whether the EC–MC interaction affects BMP9 signaling or not. To elucidate this point, we analyzed BMP9 signaling in a co-culture of several types of human primary culture ECs and MCs. The co-culture activated the Notch pathway in both types of cells in a co-culture- and BMP9-dependent manner. In HUVECs, the genes induced by BMP9 were significantly and synergistically induced in the presence of pericytes, fibroblasts or mesenchymal stem cells. The synergistic induction was greatly reduced in a non-contact condition. In fibroblasts, PDGFRB expression was potently induced in the presence of HUVECs, and BMP9 additively increased this response. Taken together, these results suggest that the EC–MC interaction potentiates BMP9 signaling both in ECs and MCs and plays a critical role in the maintenance of proper vessel functions.