Expression of the Cartilage Derived Anti-Angiogenic Factor Chondromodulin-I Decreases in the Early Stage of Experimental Osteoarthritis

TADASHI HAYAMI, HARUKO FUNAKI, KIYOSHI YAOEDA, KAORI MITUI, HIROSHI YAMAGIWA, KUNIHIKO TOKUNAGA, HIROSHI HATANO, JUN KONDO,YUJI HIRAKI, TADASHI YAMAMOTO, LE T. DUONG, and NAOTO ENDO

ABSTRACT.

Objective. Chondromodulin-I (ChM-I), a cartilage derived anti-angiogenic factor, has been shown to regulate the vascular invasion during endochondral bone formation. We evaluated the expression and localization of ChM-I in articular cartilage during the progression of osteoarthritis (OA) in the rat, and correlated ChM-I expression with the increase in vascular invasion into OA articular cartilage.

Methods. Expression of ChM-I, type II collagen, basic fibroblast growth factor, vascular endothelial growth factor (VEGF), and matrix metalloproteinases MMP-9 and MMP-13 were examined in articular cartilage of intact growing and adult rats and in the surgically induced OA model using in situ hybridization, Western blot analysis, and immunohistochemistry. Co-immunostaining for ChM-I and CD-31 was performed to localize ChM-I and neovascularization in articular cartilage at advanced stage of OA.

Results. Abundant expression of ChM-I protein was detected in avascular regions of the developing and adult healthy articular cartilage. In early OA, ChM-I expression decreased in the superficial zone of articular cartilage, while levels of proteoglycan and type II collagen were comparable to control. In advanced OA, ChM-I expression was reduced in all zones of articular cartilage, and the number of VEGF-expressing cells was increased. Immunohistochemical studies showed that vascular invasion occurred in proximity to chondrocytes with high expression of pro-angiogenic markers, and decreased expression of ChM-I.

Conclusion. High expression of ChM-I was detected in articular cartilage of growing and normal adult joints, implicating its role in the maintenance of avascularity of intact articular cartilage. Expression of ChM-I decreased, while expression of VEGF and other pro-angiogenic factors increased, in OA cartilage. These findings suggest the loss of ChM-I from articular cartilage might be responsible in part for promoting blood vessel invasion into the cartilage during progression of OA. (J Rheumatol 2003;30:2207-17)

Key Indexing Terms:

CHONDROMODULIN-I
ARTICULAR CARTILAGE
OSTEOARTHRITIS
ANGIOGENESIS INHIBITOR

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From the Department of Orthopedic Surgery, Niigata University School of Medicine (NUSM), Niigata, Japan.

T. Hayami, MD, PhD, Department of Orthopedic Surgery, NUSM, Department of Bone Biology and Osteoporosis Research, Merck Research Laboratories, West Point, Pennsylvania, USA; H. Funaki, MD, PhD; K. Yaoeda, MD, PhD, Department of Pathology, Institute of Nephrology, NUSM; K. Mitui PhD; J. Kondo, PhD; T. Yamamoto, MD, PhD, Research Center, Mitsubishi Chemical Corporation, Kanagawa, Japan; H. Yamagiwa, MD, PhD; K. Tokunaga, MD, PhD; H. Hatano, MD, PhD; N. Endo, MD, PhD, Department of Orthopedic Surgery, NUSM; Y. Hiraki, PhD, Department of Molecular Interaction and Tissue Engineering, Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan; L.T. Duong, PhD, Department of Bone Biology and Osteoporosis Research, Merck Research Laboratories, West Point, PA.

Address reprint requests to Dr. T. Hayami, Department of Bone Biology and Osteoporosis Research, Merck Research Laboratories, West Point, PA 19486, USA.

Submitted September 19, 2002; revision accepted February 3, 2003.

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