This is a competitive renewal of a grant proposal that during the initial funding period defined the importance of RANKL in the osteolysis that occurs around total joint replacements. There are currently more than 400,000 arthroplasties performed annually in the U.S. to treat this condition. Since up to 20% of arthroplasties require revision surgery due to aseptic loosening, this complication of arthritic treatment constitutes a major source of the morbidity, and represents billions of dollars in health care costs. During the last funding period, our work defined the interfascial membrane synovial fibroblast as a major source of RANKL. Preliminary data show that RANKL expression is dependent upon the stimulation of COX-2 and PGE2 production by Ti particles. Moreover, our findings suggest that the EP4 receptor is involved in the induction of RANKL in synovial fibroblasts.
Aim 1 defines the signaling mechanisms through which particulate debris stimulate COX-2 in synovial fibroblasts and initiates intracellular signals leading to the expression of RANKL. Our hypothesis is that the transcription factor NFicB initiates the synovial fibroblast response to particles and is necessary for COX-2 induction.
Aim 2 assesses in vitro responses to particles in synovial fibroblast from mice lacking the various EP receptors and examines the ability of these cells to stimulate osteoclastogenesis in co-cultures with osteoclast precursors. We anticipate that the EP4 receptor will be required for RANKL induction and osteoclast formation by Ti treated synovial fibroblasts. Finally, Aim 3 uses an in vivo model of calvarial bone loss in mice lacking EP receptor signaling to definitively address signals involved in RANKL induction, osteoclast formation, gene expression, and osteolysis. The role of the synovial fibroblast will be confirmed by conditional deletion of the EP4 receptor in fibroblasts. Thus through a series of highly integrated in vitro and in vivo experiments, the competitive renewal advances the findings of the initial funding period. The use of transgenic models and state of the art methods will characterize the sequential events of NFicB activation, COX-2 and PGES1 expression, PGE2 secretion, EP4 receptor binding, and RANKL expression in SF as a critical event in osteolysis. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
2R01AR046545-05
Application #
6988424
Study Section
Special Emphasis Panel (ZRG1-MOSS-A (04))
Program Officer
Panagis, James S
Project Start
1999-12-01
Project End
2010-06-30
Budget Start
2005-08-16
Budget End
2006-06-30
Support Year
5
Fiscal Year
2005
Total Cost
$336,596
Indirect Cost
Name
University of Rochester
Department
Orthopedics
Type
Schools of Dentistry
DUNS #
041294109
City
Rochester
State
NY
Country
United States
Zip Code
14627
Zhang, Minjie; Feigenson, Marina; Sheu, Tzong-jen et al. (2015) Loss of the PGE2 receptor EP1 enhances bone acquisition, which protects against age and ovariectomy-induced impairments in bone strength. Bone 72:92-100
Ben Arav, Ayelet; Pelled, Gadi; Zilberman, Yoram et al. (2012) Adeno-associated virus-coated allografts: a novel approach for cranioplasty. J Tissue Eng Regen Med 6:e43-50
Yazici, Cemal; Takahata, Masahiko; Reynolds, David G et al. (2011) Self-complementary AAV2.5-BMP2-coated femoral allografts mediated superior bone healing versus live autografts in mice with equivalent biomechanics to unfractured femur. Mol Ther 19:1416-25
Li, Dan; Gromov, Kirill; Proulx, Steven T et al. (2010) Effects of antiresorptive agents on osteomyelitis: novel insights into the pathogenesis of osteonecrosis of the jaw. Ann N Y Acad Sci 1192:84-94
Mensah, Kofi A; Ritchlin, Christopher T; Schwarz, Edward M (2010) RANKL induces heterogeneous DC-STAMP(lo) and DC-STAMP(hi) osteoclast precursors of which the DC-STAMP(lo) precursors are the master fusogens. J Cell Physiol 223:76-83
Li, Jie; Kuzin, Igor; Moshkani, Safiehkhatoon et al. (2010) Expanded CD23(+)/CD21(hi) B cells in inflamed lymph nodes are associated with the onset of inflammatory-erosive arthritis in TNF-transgenic mice and are targets of anti-CD20 therapy. J Immunol 184:6142-50
Papuga, M Owen; Proulx, Steven T; Kwok, Edmund et al. (2010) Chronic axial compression of the mouse tail segment induces MRI bone marrow edema changes that correlate with increased marrow vasculature and cellularity. J Orthop Res 28:1220-8
Mensah, Kofi A; Mathian, Alexis; Ma, Lin et al. (2010) Mediation of nonerosive arthritis in a mouse model of lupus by interferon-alpha-stimulated monocyte differentiation that is nonpermissive of osteoclastogenesis. Arthritis Rheum 62:1127-37
Mensah, Kofi A; Li, Jie; Schwarz, Edward M (2009) The emerging field of osteoimmunology. Immunol Res 45:100-13
Ritchlin, Christopher T; Proulx, Steven; Schwarz, Edward S (2009) Translational perspectives on psoriatic arthritis. J Rheumatol Suppl 83:30-4

Showing the most recent 10 out of 49 publications