2. Academic Validation
  3. Chemical inhibitors of c-Met receptor tyrosine kinase stimulate osteoblast differentiation and bone regeneration

Chemical inhibitors of c-Met receptor tyrosine kinase stimulate osteoblast differentiation and bone regeneration

  • Eur J Pharmacol. 2017 Jul 5;806:10-17. doi: 10.1016/j.ejphar.2017.03.032.
Jung-Woo Kim 1,  Mi Nam Lee 1,  Byung-Chul Jeong 2,  Sin-Hye Oh 1,  Min-Suk Kook 3,  Jeong-Tae Koh 4
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 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.
  • 4 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.
PMID: 28322831 DOI: 10.1016/j.ejphar.2017.03.032
Abstract

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.

Keywords

Bone regeneration; Osteoblast differentiation; Runx2; SGX523 (PubChem CID: 24779724); SYN1143 (PubChem CID: 16757524); c-Met inhibitor.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-18307
    99.36%, Dual c-Met/RON Inhibitor