1. Molecular regulation of bone erosion in rheumatoid arthritis.

Description: This project delineates the molecular events underlying development and progression of bone erosion in a mouse model of rheumatoid arthritis. In studies completed we have identified the transcription factor NF-kB as a target for inhibiting bone erosion. The primary goal is to design signaling-based therapies for RA.

2. Molecular regulation of inflammatory osteoclastogenesis.

A) Description: Inflammatory osteoclastogenesis is the result of superimposed action of pro- and anti inflammatory cytokine on basal osteoclast activity. We investigate the regulatory mechanisms of exacerbated osteoclast activity following inflammatory stimulation (TNF, LPS) and blockade with anti-inflammatory cytokine, primarily interleukin-4 and down stream transcription factors.

B) Description: Identify molecular motifs within the IKK signalsome (IKK2 and IKKgamma (NEMO)) which are essential mediators of the inflammatory response. This approach will allow the design of strategies to inhibit signals transmitted by these domains and abolish subsequent signals. These kinases (IKKs) are essential components of the IKK complex and are absolutely required for NF-kappaB activation.

3.  Molecular mechanisms of anti-inflammatory cytokines and their role as potent anti-osteoclastic agents. In this area, we have established that the T-lymphocyte secreted interleukin-4 inhibits NF-kappaB activation and osteoclast formation. This process is dependent upon activation of another transcription factor termed STAT6 (signal transducer and activator of transcription 6) which in this case acts as a repressor of transcription. Thus, STAT6-based design is being investigated as a potential therapy for inflammatory bone loss. Some of our published data show that certain forms of STAT6 are potent inhibitors of inflammatory bone loss in an arthritic mouse model. 

4.  Mechanisms of particle induction of osteoclasts and osteolysis.

Description: This project investigates the signaling pathways transmitted by PMMA and Titanium particles in osteoclast precursors and their contribution to development of osteolysis in calvarial mouse model of the disease. Several mediators have been identified, such as tumor necrosis factor-alpha, Interleukin-1, receptor activator of NF-kB, and down stream inflammatory regulators, primarily NF-kB and AP-1 transcription factors. Stimulation of immune (T) cells is also under investigation.