The long-term objective of our research is to achieve reproducible repair and regeneration of articular cartilage. Regeneration and repair of tissues in general recapitulates embryonic development and morphogenesis. Hence, factors involved in morphogenesis and development may be of utility in regeneration of adult tissues. Bone and articular cartilage are adjacent tissues. Yet bone has considerable potential for repair and articular cartilage is recalcitrant to repair. We have undertaken a systematic investigation of endogenous morphogens and cytokines for articular cartilage repair. Previously, we identified bone morphogenetic proteins (BMPs) and cartilage-derived morphogenetic proteins (CDMPs) as chondrogenic morphogens. Recently we identified a novel cytokine chondroleukin in articular cartilage. The proposed research will investigate the cell biology of the novel cytokine chondroleukin, a protein of 180 amino acid residues with 40% homology to human Interleukin 17. Therefore, chondroleukin is also known as IL-17B. In addition, we have identified and cloned a novel lL-17 receptor-like molecule (IL-17RL) that is expressed in articular cartilage. This receptor is expressed both as membrane-bound and soluble decoy receptor by alternative splicing of RNA transcripts. We hypothesize that chondroleukin (IL-17B) and its functional receptors form a cytokine signaling system that modulates BMP- and CDMP-induced chondrogenesis, differentiation, and maintenance of matrix homeostasis.
The Specific Aims of our investigation are:
Aim 1. To determine the anabolic and catabolic targets of lL-17B (chondroleukin) in articular cartilage homeostasis.
Aim 2 A. To identify the cognate receptors of lL-17B in articular chondrocytes.
Aim 2 B. To examine the hypothesis that the novel lL-17 receptor-like molecule (IL-1 7RL) is a functional receptor in articular cartilage.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR047345-04
Application #
6927010
Study Section
Orthopedics and Musculoskeletal Study Section (ORTH)
Program Officer
Tyree, Bernadette
Project Start
2002-08-01
Project End
2007-04-30
Budget Start
2005-08-01
Budget End
2007-04-30
Support Year
4
Fiscal Year
2005
Total Cost
$273,983
Indirect Cost
Name
University of California Davis
Department
Orthopedics
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
Ryan, James A; Eisner, Eric A; DuRaine, Grayson et al. (2009) Mechanical compression of articular cartilage induces chondrocyte proliferation and inhibits proteoglycan synthesis by activation of the ERK pathway: implications for tissue engineering and regenerative medicine. J Tissue Eng Regen Med 3:107-16
Dunn, Walter; DuRaine, Grayson; Reddi, A Hari (2009) Profiling microRNA expression in bovine articular cartilage and implications for mechanotransduction. Arthritis Rheum 60:2333-9
Yamane, Shintaro; Reddi, A Hari (2008) Induction of chondrogenesis and superficial zone protein accumulation in synovial side population cells by BMP-7 and TGF-beta1. J Orthop Res 26:485-92
Yamane, Shintaro; Cheng, Ewana; You, Zongbing et al. (2007) Gene expression profiling of mouse articular and growth plate cartilage. Tissue Eng 13:2163-73
Neu, Corey P; Khalafi, Afshin; Komvopoulos, Kyriakos et al. (2007) Mechanotransduction of bovine articular cartilage superficial zone protein by transforming growth factor beta signaling. Arthritis Rheum 56:3706-14
Niikura, Takahiro; Reddi, A Hari (2007) Differential regulation of lubricin/superficial zone protein by transforming growth factor beta/bone morphogenetic protein superfamily members in articular chondrocytes and synoviocytes. Arthritis Rheum 56:2312-21
Hattori, Shintaro; Oxford, Carol; Reddi, A Hari (2007) Identification of superficial zone articular chondrocyte stem/progenitor cells. Biochem Biophys Res Commun 358:99-103
Reddi, A Hari (2006) Aging, osteoarthritis and transforming growth factor-beta signaling in cartilage. Arthritis Res Ther 8:101
You, Zongbing; Shi, Xu-Bao; DuRaine, Grayson et al. (2006) Interleukin-17 receptor-like gene is a novel antiapoptotic gene highly expressed in androgen-independent prostate cancer. Cancer Res 66:175-83
Reddi, A H (2005) BMPs: from bone morphogenetic proteins to body morphogenetic proteins. Cytokine Growth Factor Rev 16:249-50

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