Abstract

More than 400,000 arthroplasties are performed annually in the US and up to 20 percent of these require revision surgery due to aseptic loosening. This complication constitutes a major source of morbidity and represents billions of dollars in health care costs. This proposal is designed to (1) define the role of TNFalpha/NFkB/RANK signal transduction in the disease process; and (2) develop a gene therapy protocol targeted to block the TNFalpha/NFkB/RANK mediated inflammatory bone resorption as a potential treatment for aseptic loosening. The hypothesis to be studied is that (i) particles stimulate NFkB activation leading to induction of TNFalpha; (ii) TNFalpha amplifies the inflammatory response as a paracrine mediator of NFkB stimulation; (iii) macrophage-secreted inflammatory mediators stimulate RANK ligand secretion in stromal cells; and (iv) RANK ligand stimulates osteoclastogenesis and bone resorption. It is the applicant group's hypothesis that TNFR-Ig primarily inhibits inflammation and directly inhibits osteoclastogenesis and bone resorption, while RANK-Ig/OPG are direct regulators of osteoclast formation, activation and apoptosis. These hypotheses will be investigated in a series of in vitro and in vivo experiments that include examination of the effects of particles on NFkB activation and cytokine secretion in cell lines genetically engineered to have deficient NFkB signaling, as well as in cells treated with TNFR-Ig and RANK-Ig. The effect of these proteins on macrophage induced (i) stromal cell expression of RANK ligand and OPG; (ii) osteoclastogenesis; and (iii) bone resorption will be assessed. Finally, they will investigate adeno-associated viral (AAV) gene transfer as an effective delivery system for TNFR-Ig and OPG. The applicants hypothesize that particles will stimulate AAV second strand synthesis and lead to target protein expression that will be sustained and occur after a period of dormancy. The hypothesis is that the AAV-transduced target proteins, TNFR-Ig and OPG, inhibit particle-induced inflammatory bone resorption in vivo, expecting that the effects will be greatest when used in combination, due to their actions at different stages in the process of inflammatory bone resorption.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR046545-03
Application #
6534491
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Panagis, James S
Project Start
2000-09-01
Project End
2004-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
3
Fiscal Year
2002
Total Cost
$342,222
Indirect Cost

  Institution

Name
University of Rochester
Department
Orthopedics
Type
Schools of Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627

  Publications

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, 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
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
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