title: CCL7 is a protective factor secreted by mechanically loaded osteocytes.
abstract: In a search for factors up-regulated by mechanical strain in osteocytes, we discovered that chemokine (C-C motif) ligand 7 (CCL7), a chemotactic myokine, was highly expressed in MLO-Y4 osteocyte-like cells. Although MLO-Y4 cells secrete potent chemotactic factors for osteoclast precursors, CCL7 was not responsible for this activity. CCL7 was increased in osteocytes in response to tooth movement in vivo. Since mechanical loading plays a crucial role in maintaining osteocyte viability, CCL7 was tested for protective activity and found to be protective against cell death induced by dexamethasone and etoposide. CCL7 specific antibody partially, but in combination with indomethacin, completely abrogated the protective effects of fluid flow shear stress against dexamethasone-induced cell death. CCL7 activated the β-catenin pathway through phosphorylation of glycogen synthase kinase 3 (GSK-3), suggesting that this pathway is responsible for the observed protective effects. A related cytokine, CCL2, also produced by MLO-Y4 cells but not regulated by mechanical loading, proved to be more potent and protected against cell death induced by not only dexamethasone, but also by Tumor Necrosis Factor α (TNFα). Whereas osteocytes may produce CCL2 in constitutively low levels, a major function of mechanically induced CCL7 may be to selectively protect osteocytes in an autocrine manner against glucocorticoid-induced cell death.
authors.affiliation: Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, MO, USA kitasey@umkc.edu.
authors.forename: Y
authors.initials: Y
authors.lastname: Kitase
authors.affiliation: Endocrinology, Internal Medicine, Eulji University School of Medicine, Daejeon City, Republic of Korea.
authors.forename: S
authors.initials: S
authors.lastname: Lee
authors.affiliation: Orthodontics.
authors.forename: J
authors.initials: J
authors.lastname: Gluhak-Heinrich
authors.affiliation: Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, MO, USA.
authors.forename: M L
authors.initials: ML
authors.lastname: Johnson
authors.affiliation: Periodontics and Cellular and Structural Biology, University of Texas Health Science Center at San Antonio, San Antonio, TX, USA.
authors.forename: S E
authors.initials: SE
authors.lastname: Harris
authors.affiliation: Oral and Craniofacial Sciences, School of Dentistry, University of Missouri-Kansas City, Kansas City, MO, USA.
authors.forename: L F
authors.initials: LF
authors.lastname: Bonewald
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D000906:Antibodies / Q000494:pharmacology; D019898:Autocrine Communication / Q000502:physiology; D001696:Biomechanical Phenomena; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000502:physiology; D018932:Chemokine CCL2 / Q000378:metabolism; D054410:Chemokine CCL7 / Q000276:immunology / Q000378:metabolism*; D003907:Dexamethasone / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D005938:Glucocorticoids / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000187:drug effects; D007213:Indomethacin / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000378:metabolism*; D010766:Phosphorylation; D020011:Protective Agents / Q000378:metabolism*; D012212:Rheology; D013314:Stress, Mechanical; D014087:Tooth Movement Techniques / Q000295:instrumentation; D059005:Topoisomerase II Inhibitors / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology; D051176:beta Catenin / Q000187:drug effects
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D000906:Antibodies; C491768:Ccl2 protein, mouse; C515451:Ccl7 protein, mouse; D018932:Chemokine CCL2; D054410:Chemokine CCL7; D005938:Glucocorticoids; D020011:Protective Agents; D059005:Topoisomerase II Inhibitors; D014409:Tumor Necrosis Factor-alpha; D051176:beta Catenin; D005047:Etoposide; D003907:Dexamethasone; D038362:Glycogen Synthase Kinase 3; D007213:Indomethacin
keywords: TNFα; cell death; chemokine; glucocorticoid; mechanical stress; tooth movement