Calcification of the pericellular matrix in articular cartilage is highly prevalent in osteoarthritis (OA) and aging. The deposited crystals of calcium pyrophosphate dihydrate (CPPD) and/or hydroxyapatite (HA) can be released from the cartilage matrix and can trigger inflammation and promote the expression of connective tissue degrading enzymes, thereby contributing to further cartilage degradation. The expression of C-X-C chemokines including IL-8 and its receptors CXCR-1 and CXCR-2 has recently been demonstrated in chondrocytes, and these mediators all are up regulated in OA cartilage in vivo. Our preliminary studies demonstrated that IL-8 induces MMP-13, and promotes features of hypertrophic differentiation (type X collagen expression and transglutaminase activation) associated with heightened matrix calcification in vitro in articular chondrocytes. Base on our new data on IL-8 signaling and function in leukocytes and articular chondrocytes, we propose to advance understanding of how IL-8 signaling via CXCR1 and/or CXCR2 transduces hypertrophy and matrix calcification in articular chondrocytes. We will test the following hypothetical model: 1) Activation of p38 MAPK is essential for induction of the features of hypertrophic differentiation, matrix calcification and MMP-13 by IL-8 in articualr chondrocytes. 2) Pyk2 tyrosine kinase, associated with a Src family tyrosine kinase, plays a central role in activation of p38 MAPK in mediating such effects of IL-8 in articular chondrocytes. 3) CXCR1 and CXCR2 signal differentially to transduce the stimulatory effect of IL-8. 4) Phospholipase C (PLC) transduces CXCR1 and CXCR2 signaling to induce intracellular Ca2+ increase and protein kinase C (PKC) activation, which in turn, activate Pyk2 and alpha5beta1 integrin, respectively. 5) FAK, activated through alpha5-beta1 integrin, and Pyk2 differentially mediate CXCR1 and CXCR2 signaling to induce hypertrophic differentiation, matrix calcification and MMP-13 in articular chondrocytes. The completion of this study has the potential to provide a foundation for novel chemokine and signal transduction-based therapeutic strategies for treatment of chondrocalcinosis in OA and aging.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Small Research Grants (R03)
Project #
5R03AR049416-02
Application #
6789990
Study Section
Special Emphasis Panel (ZAR1-RJB-A (O3))
Program Officer
Tyree, Bernadette
Project Start
2003-08-15
Project End
2006-07-31
Budget Start
2004-08-01
Budget End
2005-07-31
Support Year
2
Fiscal Year
2004
Total Cost
$66,100
Indirect Cost
Name
Veterans Medical Research Fdn/San Diego
Department
Type
DUNS #
933863508
City
San Diego
State
CA
Country
United States
Zip Code
92161
Nguyen, M T Audrey; Favelyukis, Svetlana; Nguyen, Anh-Khoi et al. (2007) A subpopulation of macrophages infiltrates hypertrophic adipose tissue and is activated by free fatty acids via Toll-like receptors 2 and 4 and JNK-dependent pathways. J Biol Chem 282:35279-92
Liu-Bryan, Ru; Terkeltaub, Robert (2006) Evil humors take their toll as innate immunity makes gouty joints TREM-ble. Arthritis Rheum 54:383-6
Scott, Peter; Ma, Hong; Viriyakosol, Suganya et al. (2006) Engagement of CD14 mediates the inflammatory potential of monosodium urate crystals. J Immunol 177:6370-8
Liu-Bryan, Ru; Pritzker, Kenneth; Firestein, Gary S et al. (2005) TLR2 signaling in chondrocytes drives calcium pyrophosphate dihydrate and monosodium urate crystal-induced nitric oxide generation. J Immunol 174:5016-23
Cecil, Denise L; Rose, David M; Terkeltaub, Robert et al. (2005) Role of interleukin-8 in PiT-1 expression and CXCR1-mediated inorganic phosphate uptake in chondrocytes. Arthritis Rheum 52:144-54
Liu-Bryan, Ru; Scott, Peter; Sydlaske, Anya et al. (2005) Innate immunity conferred by Toll-like receptors 2 and 4 and myeloid differentiation factor 88 expression is pivotal to monosodium urate monohydrate crystal-induced inflammation. Arthritis Rheum 52:2936-46
Liu-Bryan, Ru; Pay, Salih; Schraufstatter, Ingrid U et al. (2005) The CXCR1 tail mediates beta1 integrin-dependent cell migration via MAP kinase signaling. Biochem Biophys Res Commun 332:117-25
Liu, Ru; Liote, Frederic; Rose, David M et al. (2004) Proline-rich tyrosine kinase 2 and Src kinase signaling transduce monosodium urate crystal-induced nitric oxide production and matrix metalloproteinase 3 expression in chondrocytes. Arthritis Rheum 50:247-58