title: Isopsoralen Induces Differentiation of Prechondrogenic ATDC5 Cells via Activation of MAP Kinases and BMP-2 Signaling Pathways.
abstract: Endochondral bone formation is the process by which mesenchymal cells condense to become chondrocytes, which ultimately form new bone. The process of chondrogenic differentiation and hypertrophy is critical for bone formation and as such is regulated by many factors. In this study, we aimed to indentify novel factors that regulate chondrogenesis. We investigated the possible role of isopsoralen in induction of chondrogenic differentiation in clonal mouse chondrogenic ATDC5 cells. Isopsoralen treatment stimulated the accumulation of cartilage nodules in a dose-dependent manner. Further, ATDC5 cells treated with isopsoralen were stained more intensely with Alcian blue than control cells, suggesting that isopsoralen increases the synthesis of matrix proteoglycans. Similarly, isopsoralen markedly induced the activation of alkaline phosphatase activity compared with control cells. Isopsoralen enhanced the expressions of chondrogenic marker genes such as collagen II, collagen X, OCN, Smad4 and Sox9 in a time-dependent manner. Furthermore, isopsoralen induced the activation of extracellular signal-regulated kinase (ERK) and p38 MAP kinase, but not that of c-jun N-terminal kinase (JNK). Isopsoralen significantly enhanced the protein expression of BMP-2 in a time-dependent manner. PD98059 and SB 203580, inhibitors of ERK and p38 MAPK, respectively, decreased the number of stained cells treated with isopsoralen. Taken together, these results suggest that isopsoralen mediates a chondromodulating effect by BMP-2 or MAPK signaling pathways, and is therefore a possible therapeutic agent for bone growth disorders.
authors.affiliation: Department of Dental Pharmacology, School of Dentistry and Institute of Oral Bioscience, Brain Korea 21 Project, Chonbuk National University, Jeonju 561-756 ; College of Pharmacy, Woosuk University, Wonju 565-701.
authors.forename: Liang
authors.initials: L
authors.lastname: Li
authors.forename: Jae Soon
authors.initials: JS
authors.lastname: Eun
authors.forename: Manoj
authors.initials: M
authors.lastname: Nepal
authors.forename: Jae-Ha
authors.initials: JH
authors.lastname: Ryu
authors.forename: Hyoung Kwon
authors.initials: HK
authors.lastname: Cho
authors.forename: Bo-Yun
authors.initials: BY
authors.lastname: Choi
authors.forename: Yunjo
authors.initials: Y
authors.lastname: Soh
keywords: ATDC5 cells; BMP-2; Chondrogenesis; Growth disorders; Isopsoralen; MAP kinases