title: Simvastatin inhibits CD44 fragmentation in chondrocytes.
abstract: In human osteoarthritic chondrocytes, the hyaluronan receptor CD44 undergoes proteolytic cleavage at the cell surface. CD44 cleavage is thought to require transit of CD44 into cholesterol-rich lipid rafts. The purpose of this study was to investigate whether statins exert a protective effect on articular chondrocytes due to diminution of cholesterol. Three model systems of chondrocytes were examined including human HCS-2/8 chondrosarcoma cells, human osteoarthritic chondrocytes and normal bovine articular chondrocytes. Treatment with IL-1β + Oncostatin M resulted in a substantial increase in CD44 fragmentation in each of the three chondrocyte models. Pre-incubation with simvastatin prior to treatment with IL-1β + Oncostatin M decreased the level of CD44 fragmentation, decreased the proportion of CD44 that transits into the lipid raft fractions, decreased ADAM10 activity and diminished the interaction between CD44 and ADAM10. In HCS-2/8 cells and bovine articular chondrocytes, fragmentation of CD44 was blocked by the knockdown of ADAM10. Inhibition of CD44 fragmentation by simvastatin also resulted in improved retention of pericellular matrix. Addition of cholesterol and farnesyl-pyrophosphate reversed the protective effects of simvastatin. Thus, the addition of simvastatin exerts positive effects on chondrocytes including reduced CD44 fragmentation and enhanced the retention of pericellular matrix.
authors.affiliation: Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan; Department of Anatomy and Cell Biology, The Brody School of Medicine, East Carolina University, 600 Moye Blvd., Greenville, NC 27834, USA.
authors.forename: Kenya
authors.initials: K
authors.lastname: Terabe
authors.affiliation: Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan. Electronic address: nobunori@med.nagoya-u.ac.jp.
authors.forename: Nobunori
authors.initials: N
authors.lastname: Takahashi
authors.affiliation: Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Toki
authors.initials: T
authors.lastname: Takemoto
authors.affiliation: Department of Anatomy and Cell Biology, The Brody School of Medicine, East Carolina University, 600 Moye Blvd., Greenville, NC 27834, USA.
authors.forename: Warren
authors.initials: W
authors.lastname: Knudson
authors.affiliation: Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Ishiguro
authors.affiliation: Department of Orthopedic Surgery, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan.
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Kojima
mesh_terms: D000072197:ADAM10 Protein / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D000818:Animals; D002358:Cartilage, Articular / Q000187:drug effects / Q000473:pathology*; D002417:Cattle; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism; D002784:Cholesterol / Q000737:chemistry; D019902:Chondrocytes / Q000187:drug effects / Q000378:metabolism*; D002813:Chondrosarcoma / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D021962:Membrane Microdomains / Q000737:chemistry; D008565:Membrane Proteins / Q000378:metabolism; D008798:Mevalonic Acid / Q000737:chemistry; D053683:Oncostatin M / Q000737:chemistry; D011106:Polyisoprenyl Phosphates / Q000737:chemistry; D034741:RNA, Small Interfering / Q000378:metabolism; D012717:Sesquiterpenes / Q000737:chemistry; D019821:Simvastatin / Q000737:chemistry*
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D053583:Interleukin-1beta; D008565:Membrane Proteins; D011106:Polyisoprenyl Phosphates; D034741:RNA, Small Interfering; D012717:Sesquiterpenes; D053683:Oncostatin M; C004808:farnesyl pyrophosphate; D002784:Cholesterol; D019821:Simvastatin; D053829:Amyloid Precursor Protein Secretases; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D008798:Mevalonic Acid
keywords: ADAM10; CD44; Chondrocyte; Lipid raft; Pericellular matrix; Statin