During cartilage degeneration associated with osteoarthritis, chondrocyte proliferation (cloning), hypertrophy, and calcification occur, resembling a recapitulation of the events which occur during endochondral bone formation. Recently a number of new genes which are expressed during chondrocyte maturation have been characterized, including PTHrP, PTH/PTHrP receptor, indian hedgehog (IHH), annexin V, and BMP6. We have also identified NHE1 (a Na+/H+ exchanger isoform) as a candidate molecule under regulation of PTHrP and BMP6 which drives the chondrocyte hypertrophic volume increase. We have identified PTHrP and BMP6, which are not expressed in normal adult articular cartilage, in human OA cartilage. This has led to our overall hypothesis that cytokine production in OA leads to activation of the chondrocyte maturation pathway. Elements of this pathway, including cell proliferation, MMP production, hypertrophy, matrix turnover, and apoptosis, may contribute to the pathophysiology of OA. Understanding the regulation of the maturational pathway may therefore lead to new diagnostic markers or therapeutic targets in OA.
Specific Aim 1 will use well characterized in vitro chondrocyte culture models to study the role of IHH, PTHrP, and the PRHrP receptor in the initiation of maturation.
Specific Aim 2 will examine the effect of TNF and other cytokines on gene expression associated with chondrctye maturation.
Specific Aim 3 will correlate the in vitro findings with tissue-based studies of chondrocyte maturation using a TNF overexpression murine arthritis model, and human OA cartilage. Thus, this proposal will examine the inter-relationships between BMPs, PTHrP and their coordinate role in the regulation of chondrocyte maturation during endochondral ossification.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR045700-04
Application #
6488886
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Tyree, Bernadette
Project Start
1999-01-15
Project End
2003-12-31
Budget Start
2002-01-01
Budget End
2003-12-31
Support Year
4
Fiscal Year
2002
Total Cost
$289,887
Indirect Cost
Name
University of Rochester
Department
Orthopedics
Type
Schools of Dentistry
DUNS #
208469486
City
Rochester
State
NY
Country
United States
Zip Code
14627
Kim, Kyung-Ok; Sampson, Erik R; Maynard, Robert D et al. (2012) Ski inhibits TGF-ýý/phospho-Smad3 signaling and accelerates hypertrophic differentiation in chondrocytes. J Cell Biochem 113:2156-66
Holz, Jonathan D; Beier, Eric; Sheu, Tzong-Jen et al. (2012) Lead induces an osteoarthritis-like phenotype in articular chondrocytes through disruption of TGF-? signaling. J Orthop Res 30:1760-6
Sampson, Erik R; Hilton, Matthew J; Tian, Ye et al. (2011) Teriparatide as a chondroregenerative therapy for injury-induced osteoarthritis. Sci Transl Med 3:101ra93
Sampson, Erik R; Beck, Christopher A; Ketz, John et al. (2011) Establishment of an index with increased sensitivity for assessing murine arthritis. J Orthop Res 29:1145-51
Mooney, Robert A; Sampson, Erik R; Lerea, Jaclyn et al. (2011) High-fat diet accelerates progression of osteoarthritis after meniscal/ligamentous injury. Arthritis Res Ther 13:R198
Wu, Qiuqian; Huang, Jason H; Sampson, Erik R et al. (2009) Smurf2 induces degradation of GSK-3beta and upregulates beta-catenin in chondrocytes: a potential mechanism for Smurf2-induced degeneration of articular cartilage. Exp Cell Res 315:2386-98
Zhu, Mei; Tang, Dezhi; Wu, Qiuqian et al. (2009) Activation of beta-catenin signaling in articular chondrocytes leads to osteoarthritis-like phenotype in adult beta-catenin conditional activation mice. J Bone Miner Res 24:12-21
Wu, Qiuqian; Chen, Di; Zuscik, Michael J et al. (2008) Overexpression of Smurf2 stimulates endochondral ossification through upregulation of beta-catenin. J Bone Miner Res 23:552-63
Wu, Qiuqian; Kim, Kyung-Ok; Sampson, Erik R et al. (2008) Induction of an osteoarthritis-like phenotype and degradation of phosphorylated Smad3 by Smurf2 in transgenic mice. Arthritis Rheum 58:3132-44
Wu, Qiuqian; Wang, Meina; Zuscik, Michael J et al. (2008) Regulation of embryonic endochondral ossification by Smurf2. J Orthop Res 26:704-12

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