title: Berberine bioisostere Q8 compound stimulates osteoblast differentiation and function in vitro.
abstract: The Q8 compound is a unique derivative of berberine. The present study investigated the functional role of Q8 to evaluate its potential for use in bone regeneration, especially in osteoblast differentiation. The safe concentration of Q8 increased BMP4-induced alkaline phosphatase (ALP) activity, and induced RNA expression of ALP, bone sialoprotein (BSP), and osteocalcin (OC). The activities of ALP-, BSP- and OC-luciferase reporters were also increased by Q8. During osteoblast differentiation, Q8 stabilized the Runx2 and Osterix protein abundance by blocking the ubiquitin-proteasome pathway, which in turn promoted Runx2 and Osterix induced transcriptional activity and subsequently increased the osteoblast differentiation. Meanwhile, depletion of Runx2 and Osterix markedly abolished the bone anabolic effect of Q8 on osteoblast differentiation. To evaluate the signal transduction pathway involved in the Q8-mediated regulation of Runx2 and Osterix, we examined the reporter assay using various kinase inhibitors. Treatment with a protein kinase A (PKA) inhibitor, H89 inhibited the Q8-mediated regulation of Runx2 and Osterix. Based on these findings, this study demonstrates that Q8 promotes the osteoblast differentiation by stabilization of Runx2/Osterix through the increased activation of PKA signaling. The enhancement of osteoblast function by Q8 may contribute to the prevention for osteoporosis.
authors.affiliation: College of Pharmacy & Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Younho
authors.initials: Y
authors.lastname: Han
authors.affiliation: College of Pharmacy & Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Yifeng
authors.initials: Y
authors.lastname: Jin
authors.affiliation: College of Pharmacy & Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Sung Ho
authors.initials: SH
authors.lastname: Lee
authors.affiliation: College of Pharmacy & Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea.
authors.forename: Daulat Bikram
authors.initials: DB
authors.lastname: Khadka
authors.affiliation: College of Pharmacy & Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea. Electronic address: wjcho@chonnam.ac.kr.
authors.forename: Won-Jea
authors.initials: WJ
authors.lastname: Cho
authors.affiliation: College of Pharmacy & Research Institute of Drug Development, Chonnam National University, Gwangju 500-757, Republic of Korea. Electronic address: kwanglee@jnu.ac.kr.
authors.forename: Kwang Youl
authors.initials: KY
authors.lastname: Lee
mesh_terms: D000818:Animals; D001599:Berberine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects; D050659:Core Binding Factor Alpha 1 Subunit / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects*; D010766:Phosphorylation / Q000187:drug effects; D055550:Protein Stability / Q000187:drug effects; D000076182:Sp7 Transcription Factor; D014157:Transcription Factors / Q000378:metabolism
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D000076182:Sp7 Transcription Factor; C479466:Sp7 protein, mouse; D014157:Transcription Factors; D001599:Berberine; D017868:Cyclic AMP-Dependent Protein Kinases
keywords: Osteoblast; Osterix; PKA; Q8; Runx2