Quinoline compound KM11073 enhances BMP-2-dependent osteogenic differentiation of C2C12 cells via activation of p38 signaling and exhibits in vivo bone forming activity

• Published in: PloS one Vol. 10; no. 3; p. e0120150
• Main Authors: Baek, Seung-hwa, Choi, Sik-Won, Park, Sang-Joon, Lee, Sang-Han, Chun, Hang-Suk, Kim, Seong Hwan
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 19.03.2015; Public Library of Science (PLoS)
• Subjects: Activation; Alkaline phosphatase; Alkaline Phosphatase - metabolism; Animal models; Animals; Biocompatibility; Biomarkers; Biomedical materials; Bone growth; Bone morphogenetic protein 2; Bone Morphogenetic Protein 2 - genetics; Bone Morphogenetic Protein 2 - metabolism; Bone Morphogenetic Protein 2 - pharmacology; Bone Morphogenetic Protein 6 - genetics; Bone Morphogenetic Protein 6 - metabolism; Bone Morphogenetic Protein 7 - genetics; Bone Morphogenetic Protein 7 - metabolism; Bone morphogenetic proteins; Cell Differentiation - drug effects; Cell growth; Cell Line; Danio rerio; Differentiation; Exhibitions; Food science; Gene expression; Health aspects; Humans; Laboratories; Mesenchyme; Mice; mRNA; Noggin protein; Osteoblastogenesis; Osteogenesis; Osteogenesis - drug effects; Osteopontin - genetics; Osteopontin - metabolism; p38 Mitogen-Activated Protein Kinases - metabolism; Pharmacology; Phosphatase; Physical properties; Physiological effects; Physiology; Piperazines - chemistry; Piperazines - pharmacology; Proteins; Quinoline; Quinolines - chemistry; Quinolines - pharmacology; Recombinant Proteins - pharmacology; Regenerative Medicine; RNA; RNA, Messenger - metabolism; Side effects; Signal Transduction - drug effects; Signaling; Skull - pathology; Smad Proteins - metabolism; Stem cells; Toxicology; Transforming Growth Factor beta - pharmacology; Zebrafish; Zebrafish - growth & development; United States > US; South Korea
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0120150

Recombinant human bone morphogenetic protein (rhBMP)-2 has been approved by the FDA for clinical application, but its use is limited due to high cost and a supra-physiological dose for therapeutic efficacy. Therefore, recent studies have focused on the generation of new therapeutic small molecules to induce bone formation or potentiate the osteogenic activity of BMP-2. Here, we show that [4-(7-chloroquinolin-4-yl) piperazino][1-phenyl-5-(trifluoromethyl)-1H-pyrazol-4-yl]methanone (KM11073) strongly enhances the BMP-2-stimulated induction of alkaline phosphatase (ALP), an early phase biomarker of osteoblast differentiation, in bi-potential mesenchymal progenitor C2C12 cells. The KM11073-mediated ALP induction was inhibited by the BMP antagonist noggin, suggesting that its osteogenic activity occurs via BMP signaling. In addition, a pharmacological inhibition study suggested the involvement of p38 activation in the osteogenic action of KM11073 accompanied by enhanced expression of BMP-2, -6, and -7 mRNA. Furthermore, the in vivo osteogenic activity of KM11073 was confirmed in zebrafish and mouse calvarial bone formation models, suggesting the possibility of its single use for bone formation. In conclusion, the combination of rhBMP-2 with osteogenic small molecules could reduce the use of expensive rhBMP-2, mitigating the undesirable side effects of its supra-physiological dose for therapeutic efficacy. Moreover, due to their inherent physical properties, small molecules could represent the next generation of regenerative medicine.