Regulation of synthesis of osteoprotegerin and soluble receptor activator of nuclear factor-kappaB ligand in normal human osteoblasts via the p38 mitogen-activated protein kinase pathway by the application of cyclic tensile strain.
Mechanical stress is thought to play an important role in bone remodeling. However, the correlation between mechanical stress and bone remodeling is poorly understood. In this context, using a model of cyclic tensile strain (CTS) toward human osteoblasts, synthesis of osteoprotegerin (OPG) and soluble receptor activator of nuclear factor-kappaB ligand (sRANKL), and the activation of mitogen-activated protein kinases (MAPKs) were examined. The application of 7%, 0.25-Hz CTS once a day for 4 h for 3 successive days simultaneously caused an increase of OPG synthesis and a decrease of sRANKL release and RANKL mRNA expression in osteoblasts. As for MAPKs activation in osteoblasts with the application of CTS, p38 MAPK was activated 10-20 min after the application of CTS, but extracellular signal-regulated kinase (ERK1/2) and c-Jun NH2-terminal kinase (JNK) were not activated by such application. Furthermore, when CTS was applied once a day for 4 h for 1, 2, or 3 successive days to osteoblasts, p38 MAPK activation was maintained during the 3-day period but ERK1/2 activation was downregulated from day to day, simultaneously. Then, when CTS was applied once a day for 4 h for 3 successive days to osteoblasts pretreated with the p38 MAPK inhibitor SB203580 for 1 h, OPG synthesis was dose-dependently suppressed and inhibition of sRANKL release and RANKL mRNA expression was abrogated. These results indicate that biological responses of OPG and sRANKL synthesis in osteoblasts to the application of CTS are regulated via the p38 MAPK pathway and suggest that CTS might modulate and regulate bone metabolism.
Kusumi
Akinori
A
Department of Dentistry and Oral Surgery, National University Corporation, Hirosaki University School of Medicine, 5 Zaifu-cho, Hirosaki 036-8562, Japan. akusumi@cc.hirosaki-u.ac.jp
Sakaki
Hirotaka
H
Kusumi
Tomomi
T
Oda
Mitsuo
M
Narita
Kenji
K
Nakagawa
Hiroshi
H
Kubota
Kohsei
K
Satoh
Hisashi
H
Kimura
Hiroto
H
D015153:Blotting, Western; D002352:Carrier Proteins / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D004797:Enzyme-Linked Immunosorbent Assay; D005786:Gene Expression Regulation; D006023:Glycoproteins / Q000096:biosynthesis* / Q000737:chemistry*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D015151:Immunoblotting; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008562:Membrane Glycoproteins / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000378:metabolism* / Q000502:physiology*; D053244:Osteoprotegerin; D017434:Protein Structure, Tertiary; D011725:Pyridines / Q000494:pharmacology; D053245:RANK Ligand; D012333:RNA, Messenger / Q000378:metabolism; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear / Q000096:biosynthesis* / Q000737:chemistry*; D018124:Receptors, Tumor Necrosis Factor / Q000096:biosynthesis* / Q000737:chemistry*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013314:Stress, Mechanical; D013718:Tensile Strength; D013997:Time Factors; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D002352:Carrier Proteins; D006023:Glycoproteins; D007093:Imidazoles; D008562:Membrane Glycoproteins; D053244:Osteoprotegerin; D011725:Pyridines; D053245:RANK Ligand; D012333:RNA, Messenger; D053246:Receptor Activator of Nuclear Factor-kappa B; D018160:Receptors, Cytoplasmic and Nuclear; D018124:Receptors, Tumor Necrosis Factor; C505686:TNFRSF11A protein, human; C506030:TNFRSF11B protein, human; C505688:TNFSF11 protein, human; D048031:JNK Mitogen-Activated Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580