title: Mechanical stress loading induces CD44 cleavage in human chondrocytic HCS-2/8 cells.
abstract: Although excessive mechanical stress loading is known to induce articular cartilage degradation, the mechanism underlying this process is unclear. The interaction between hyaluronan (HA) and its primary receptor CD44 maintains the homeostasis of articular chondrocytes. CD44 cleavage and the generation of CD44-intracellular domain (ICD) can lead to the loss of extracellular matrices in chondrocytes. Here we studied the effects of cyclic tensile strain (CTS) loading, a representative mechanical stress, on CD44 cleavage. CTS loading (1 Hz and 20% elongation for 48 h) increased ADAM10 expression and CD44 cleavage in HCS-2/8 cells, a human chondrocytic cell line. Co-treatment with a chemical ADAM10 inhibitor significantly suppressed CTS loading-induced CD44 cleavage. Chemical inhibition of transient receptor potential vanilloid 4 (TRPV4) significantly suppressed CTS loading-induced ADAM10 expression and CD44 cleavage. Conversely, chemical activation of TRPV4 increased ADAM10 expression and enhanced CD44 cleavage. Our findings suggest that CTS loading significantly increases the expression of ADAM10, which in turn enhances CD44 cleavage in HCS-2/8 cells. The primary mechanoreceptor mediating this process is TRPV4. This signature event could provide an avenue for intervention in the prevention of cartilage degradation leading to OA.
authors.affiliation: Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Kobayakawa
authors.affiliation: Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-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 Orthopaedic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
authors.forename: Yasumori
authors.initials: Y
authors.lastname: Sobue
authors.affiliation: Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
authors.forename: Kenya
authors.initials: K
authors.lastname: Terabe
authors.affiliation: Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
authors.forename: Naoki
authors.initials: N
authors.lastname: Ishiguro
authors.affiliation: Department of Orthopaedic Surgery, Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
authors.forename: Toshihisa
authors.initials: T
authors.lastname: Kojima
mesh_terms: D000072197:ADAM10 Protein / Q000378:metabolism; D000072198:ADAM17 Protein / Q000378:metabolism; D053829:Amyloid Precursor Protein Secretases / Q000378:metabolism; D002460:Cell Line; D019902:Chondrocytes / Q000378:metabolism*; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism*; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D008565:Membrane Proteins / Q000378:metabolism; D013314:Stress, Mechanical; D050916:TRPV Cation Channels / Q000378:metabolism; D013718:Tensile Strength
chemical_list: C497483:CD44 protein, human; D018960:Hyaluronan Receptors; D008565:Membrane Proteins; D050916:TRPV Cation Channels; C416986:TRPV4 protein, human; D053829:Amyloid Precursor Protein Secretases; D053511:Matrix Metalloproteinase 14; D000072197:ADAM10 Protein; C491236:ADAM10 protein, human; D000072198:ADAM17 Protein; C000606462:ADAM17 protein, human
keywords: ADAM-10; CD44 cleavage; HCS-2/8; Mechanical loading; Osteoarthritis; TRPV4