Osteoarthritis is one of the leading causes of pain and disability in the aged population due to articular cartilage damage. This warrants investigation of signaling mechanisms that could protect cartilage from degeneration and degradation. Here we show in a murine model of experimental osteoarthritis that YAP activation by transgenic overexpression or by deletion of its upstream inhibitory kinases Mst1/2 preserves articular cartilage integrity, whereas deletion of YAP in chondrocytes promotes cartilage disruption. Our work shows that YAP is both necessary and sufficient for the maintenance of cartilage homeostasis in osteoarthritis. Mechanistically, inflammatory cytokines, such as TNFα or IL-1β, trigger YAP/TAZ degradation through TAK1-mediated phosphorylation. Furthermore, YAP directly interacts with TAK1 and attenuates NF-κB signaling by inhibiting substrate accessibility of TAK1. Our study establishes a reciprocal antagonism between Hippo-YAP/TAZ and NF-κB signaling in regulating the induction of matrix-degrading enzyme expression and cartilage degradation during osteoarthritis pathogenesis.

Nasopharyngeal cancer (NPC) is an Epstein-Barr virus (EBV)-associated head and neck cancer prevalent in Asia. Although with reasons not fully understood, the intrinsic invasiveness of NPC is believed to be EBV-linked. Recently, EBV was found to induce STAT3 activation. Constitutive STAT3 activation correlated with advanced clinical staging in NPC. We hypothesized that STAT3 activation by EBV directly contributes to the intrinsic invasiveness of NPC cells. Phospho-STAT3-Tyr705 was detected in high percentage of NPC tumors (7/10 cases). Using a paired NPC cell line model, HONE-1 and the EBV-infected counterpart, HONE-1-EBV, we found that HONE-1-EBV expressed a higher level of phospho-STAT3-Tyr705 and was 11-fold more invasive than HONE-1. In HONE-1-EBV, STAT3 siRNA targeting inhibited both spontaneous and serum-induced invasion, as well as cell growth. Conversely, activation of STAT3 (by expressing an activated STAT3 mutant, namely STAT3C) in the parental HONE-1, mimicking EBV-induced STAT3 activation, significantly enhanced its invasiveness and proliferation, which was accompanied by increased expression of markers of mesenchymal status, proliferation and anti-apoptosis. Our results demonstrated that EBVinduced STAT3 activation is responsible for NPC cell proliferation and invasion. This was further confirmed by a small molecule inhibitor of JAK/STAT3, JSI-124. JSI-124 inhibited STAT3 activation in HONE-1-EBV, with subsequent growth inhibition, induction of PARP cleavage, abrogation of anchorage-independent growth and invasion. We found that EBV-independent activation of STAT3 by a growth factor, EGF, also contributed to NPC invasion. In conclusion, EBV-induced STAT3 activation directly contributes to the intrinsic invasiveness of NPC cells and STAT3 targeting may be beneficial in treating aggressive NPC. ' 2009 UICC Key words: STAT3; nasopharyngeal cancer (NPC); EBV; invasion Nasopharyngeal cancer (NPC) is a distinct type of head and neck cancer highly prevalent in Southeast Asia with a strong etiological association with the Epstein-Barr virus (EBV), a wellknown group I carcinogen. 1,2 One hundred percent of NPC cases in endemic regions are EBV positive. 3,4 NPC is also characterized by heavy lymphocyte infiltration (with rich supply of cytokines in the tumor microenvironment), high invasive and metastatic tendency. Recurrent NPC patients have high rate of distant metastasis up to 37%. [5][6][7] The underlying mechanism for its high metastatic characteristics is largely unknown. However, EBV is believed to play a major role.Signal Transducer and Activator of Transcription 3 (STAT3) is constitutively activated or overexpressed in a vast number of human cancers, including breast, lung, prostate, brain, leukemia, multiple myeloma, head and neck squamous cell carcinoma and NPC. [8][9][10][11] This pivotal transcription factor is known to be a key regulator for multiple cellular processes, including cell growth, apoptosis, metastasis, epithelial-mesenchymal transition and differentiation. STAT3 has been proposed to...

SummaryAs the most common form of joint disorder, osteoarthritis (OA) imposes a tremendous burden on health care systems worldwide. Without effective cure, OA represents a unique opportunity for innovation in therapeutic development. In contrast to traditional treatments based on drugs, proteins, or antibodies, stem cells are poised to revolutionize medicine as they possess the capacity to replace and repair tissues and organs such as osteoarthritic joints. Among different types of stem cells, mesenchymal stem cells (MSCs) are of mesoderm origin and have been shown to generate cells for tissues of the mesoderm lineage, thus, raising the hope for them being used to treat diseases such as OA. However, given their ability to differentiate into other cell types, MSCs have also been tested in treating a myriad of conditions from diabetes to Parkinson's disease, apparently of the ectoderm and endoderm lineages. There are ongoing debates whether MSCs can differentiate into lineages outside of the mesoderm and consequently their effectiveness in treating conditions from the ectoderm and endoderm lineages. In this review, we discuss the developmental origin of MSCs, their differentiation potential and immunomodulatory effects, as well as their applications in treating OA. We suggest further investigations into new therapies or combination therapies that may provide more effective treatment for bone and joint diseases. Furthermore, cell-based therapy and its associated safety and effectiveness should be carefully evaluated before clinical translation. This review provides updated information on recent approval of clinical trials and related applications of MSCs, and discusses additional efforts on cell-based therapy for treating OA and other joint and bone diseases.

In the present study, we demonstrated that joint distraction reduced the level of secondary inflammation, cartilage degeneration and subchondral bone aberrant change, joint distraction may be a strategy for slowing OA progression.