Chemical inhibitors of c-Met receptor tyrosine kinase stimulate osteoblast differentiation and bone regeneration.
The c-Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), have been recently introduced to negatively regulate bone morphogenetic protein (BMP)-induced osteogenesis. However, the effect of chemical inhibitors of c-Met receptor on osteoblast differentiation process has not been examined, especially the applicability of c-Met chemical inhibitors on in vivo bone regeneration. In this study, we demonstrated that chemical inhibitors of c-Met receptor tyrosine kinase, SYN1143 and SGX523, could potentiate the differentiation of precursor cells to osteoblasts and stimulate regeneration in calvarial bone defects of mice. Treatment with SYN1143 or SGX523 inhibited HGF-induced c-Met phosphorylation in MC3T3-E1 and C3H10T1/2 cells. Cell proliferation of MC3T3-E1 or C3H10T1/2 was not significantly affected by the concentrations of these inhibitors. Co-treatment with chemical inhibitor of c-Met and osteogenic inducing media enhanced osteoblast-specific genes expression and calcium nodule formation accompanied by increased Runx2 expression via c-Met receptor-dependent but Erk-Smad signaling independent pathway. Notably, the administration of these c-Met inhibitors significantly repaired critical-sized calvarial bone defects. Collectively, our results suggest that chemical inhibitors of c-Met receptor tyrosine kinase might be used as novel therapeutics to induce bone regeneration.
Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju 61186, Republic of Korea; Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju 61186, Republic of Korea.
Jung-Woo
JW
Kim
Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju 61186, Republic of Korea; Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju 61186, Republic of Korea.
Mi Nam
MN
Lee
Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju 61186, Republic of Korea; Department of Pharmacology, Seonam University Medical School, Namwon, Chonbuk 55724, Republic of Korea.
Byung-Chul
BC
Jeong
Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju 61186, Republic of Korea; Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju 61186, Republic of Korea.
Sin-Hye
SH
Oh
Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju 61186, Republic of Korea; Department of Oral and Maxillofacial Surgery, School of Dentistry, Chonnam National University, Gwangju 61186, Republic of Korea.
Min-Suk
MS
Kook
Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju 61186, Republic of Korea; Department of Pharmacology and Dental Therapeutics, School of Dentistry, Chonnam National University, Gwangju 61186, Republic of Korea. Electronic address: jtkoh@chonnam.ac.kr.
Jeong-Tae
JT
Koh
D041721:3T3-L1 Cells; D000818:Animals; D052160:Benzothiazoles / Q000494:pharmacology; D001861:Bone Regeneration / Q000187:drug effects*; D002113:Calcification, Physiologic / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019859:Proto-Oncogene Proteins c-met / Q000037:antagonists & inhibitors*; D011724:Pyridazines / Q000494:pharmacology; D012886:Skull / Q000166:cytology / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D014230:Triazoles / Q000494:pharmacology
C547925:6-(6-(1-methyl-1H-pyrazol-4-yl)-(1,2,4)triazolo(4,3-b)pyridazin-3-ylsulfanyl)quinoline; D052160:Benzothiazoles; D050659:Core Binding Factor Alpha 1 Subunit; D047428:Protein Kinase Inhibitors; D011724:Pyridazines; D014230:Triazoles; C000593256:tozadenant; D019859:Proto-Oncogene Proteins c-met
Bone regeneration; Osteoblast differentiation; Runx2; SGX523 (PubChem CID: 24779724); SYN1143 (PubChem CID: 16757524); c-Met inhibitor