Faculty Bibliography

Of relevance to both protective and pathogenic responses to Ag is the recent finding that soluble molecules of the innate immune system, i.e., IL-4, B cell-activation factor of the TNF family (BAFF), and C3, exhibit significant synergy in promoting the clonal expansion of human B2 cells following low-level BCR ligation. Although IL-4, BAFF, and C3dg each contribute to early cell cycle entry and progression to S phase, only BAFF promotes later sustained viability of progeny needed for continued cycling. The present study sought to further clarify the mechanisms for BAFF's multiple functions. By comparing BAFF and a proliferation-inducing ligand (APRIL) efficacy at different stages in the response (only BAFF binds BR3; both bind transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) and B cell maturation Ag, the early role was attributed to BR3, while the later role was attributed to TACI/B cell maturation Ag. Importantly, BAFF- and APRIL-promoted viability of cycling lymphoblasts was associated with sustained expression of cyclooxygenase 2 (COX-2), the rate-limiting enzyme for PGE2 synthesis, within replicating cells. Supernatants of cultures with BAFF and APRIL contained elevated PGE2. Although COX-2 inhibitors diminished daughter cell viability, exogenous PGE2 (1-1000 nM) increased the viability and recovery of lymphoblasts. Increased yield of viable progeny was associated with elevated Mcl-1, suggesting that a BAFF/APRIL --> TACI --> COX-2 --> PGE2--> Mcl-1 pathway reduces activation-related, mitochondrial apoptosis in replicating human B2 cell clones

Osteoarthritis (OA) can be a progressive, disabling disease, leading to diminished quality of life, and, for over 500,000 individuals annually in the US, total joint replacement. The etiology of OA will vary among individuals, with potential roles for systemic factors (such as genetics and obesity) as well as for local biomechanical factors (such as muscle weakness, joint laxity and traumatic injury). Joint deterioration occurs over extended periods of time, and the diverse molecular mechanisms that mediate pathogenic events of early, mid and late disease are not yet fully understood. The success of biologic therapies in the treatment of rheumatoid arthritis has demonstrated that the blockade of a single dominant cytokine or regulatory molecule can prevent cartilage destruction in a complex disease, and has raised expectations that mechanism-based treatments could also be developed for patients with OA. In this review, we will address the biological mechanisms that mediate structural damage in OA and examine current targets that are candidates for disease modification. The challenges to drug development and the obstacles to disease modification strategies will also be addressed

Prostaglandin E2 (PGE2) is a principal mediator of inflammation in diseases such as rheumatoid arthritis and osteoarthritis. Nonsteroidal anti-inflammatory medications (NSAIDs) and selective cyclooxygenase-2 (COX-2) inhibitors reduce PGE2 production to diminish the inflammation seen in these diseases, but have toxicities that may include both gastrointestinal bleeding and prothrombotic tendencies. In cells, arachidonic acid is transformed into PGE2 via cyclooxygenase (COX) enzymes and terminal prostaglandin E synthases (PGES). Accumulating data suggest that the interaction of various enzymes in the PGE2 synthetic pathway is complex and tightly regulated. In this review, we summarize the synthesis and secretion of PGE2. In particular, we focus on the three isoforms of the terminal PGES, and discuss the potential of targeting PGES as a more precise strategy for inhibiting PGE2 production

Drug discovery and delivery to retard the degeneration of joint tissues are challenging. Current treatment is generally inadequate. This commentary places in perspective the inadequacy characteristic of existing therapeutics and the promising developments embodied in the newer therapeutics administered via the oral or intra-auricular routes

The osteoarthritis disease process affects not only the cartilage but also the entire joint structure, including the synovium, bone and periarticular muscles. Characteristically, abnormal biomechanical forces result in an imbalance between chondrocyte anabolic and catabolic pathways, which ultimately leads to progressive joint destruction. Within cartilage and synovium, pro-inflammatory cytokines, particularly IL-1b and TNF-a, auto-catalytically stimulate their own production and induce chondrocytes to produce additional catabolic mediators, including proteases, chemokines, nitric oxide, and prostaglandins. The success of targeted biological therapy in rheumatoid arthritis has taught that the blockade of a single dominant cytokine can lead to remarkable clinical benefit, even in complex disease. The effectiveness of biologicals in inflammatory arthritides as disease modifying agents has increased the likelihood that similar strategies can be developed to target specific molecular mechanisms in osteoarthritis (OA). However, since the clinical development program for disease-modifying OA drugs (DMOADs) is complicated by the slow progression of disease in many patients, the introduction of DMOADs will be greatly enhanced by advances in imaging and biomarkers that serve as validated surrogate endpoints for meaningful clinical outcomes

Osteoarthritis (OA) can be a progressive disabling disease, which results from the pathological imbalance of degradative and reparative processes, with concomitant inflammatory changes. The synovium, bone, and cartilage are each well established sites involved in the pathophysiological mechanisms that lead to progressive joint degeneration. The search for disease-modifying osteoarthritis drugs, DMOADs, has been hampered by several factors, including the variable progression of disease, the lack of specificity and sensitivity of standard radiography, and the fact that the slowing of radiographic progression may not result in corresponding improvement in pain and function. As a result, there is general agreement that development of DMOADs will be facilitated by advances in imaging and the validation of chemical biomarkers. Such biomarkers should be useful tools that will identify patients at risk for disease progression and predict responses to candidate structure-modifying drugs