chondroblasts, synthesis of collagen and alkaline phosphatase during chondrogenic and osteogenic differentiation, and induction of differentiation in neural cells

Members of the transforming growth factor-β (TGF-β) superfamily are structurally related proteins which include TGFβs, activins, and bone morphogenetic proteins (BMPs) (Kawabata et al., 1998a). BMPs were originally identified as proteins in bone that induce ectopic bone and cartilage formation in vivo, but are now known as multifunctional regulators of cell growth, differentiation, and apoptosis, and to play important roles during development (Reddi, 1994; Hogan, 1996). More than a dozen proteins belong to the BMP family, which can be divided into several subgroups based on their structural similarities. Drosophila decapentaplegic gene product (DPP), BMP-2, and BMP-4 form one subgroup, Drosophila 60A, BMP5, BMP-6/Vgr-1, osteogenic protein (OP)-1/BMP-7, and OP2/BMP-8 form another subgroup, and growth/differentiation factor (GDF)-5, -6, and -7 yet another. In vitro studies have revealed that BMPs have various biological effects on different cell types, e.g. stimulation of proteoglycan synthesis in chondroblasts, synthesis of collagen and alkaline phosphatase during chondrogenic and osteogenic differentiation, and induction of differentiation in neural cells (Katagiri et al., 1994; Shukunami et al., 1996; Paralkar et al., 1992). BMP-6 was originally isolated from a murine embryonic cDNA library and was named Vgr-1, based on its homology to Xenopus Vg-1 (Lyons et al., 1989). The human and bovine homologues of Vgr-1 were subsequently isolated from bone and named BMP-6 (Celeste et al., 1990). Expression of the BMP-6 mRNA in mammals was demonstrated in various cell types of the nervous system, growth plate chondrocytes, and epidermis (Lyons et al., 1989; Jones et al., 1991). BMP-6 protein is predominantly expressed in mature chondrocytes during endochondral ossification (Gitelman et al., 1994). BMP6 stimulates expression of chondrogenic and osteogenic phenotypes in vitro (Gitelman et al., 1995; Yamaguchi et al., 1996), and induces cartilage and bone formation in vivo 3519 Journal of Cell Science 112, 3519-3527 (1999) Printed in Great Britain © The Company of Biologists Limited 1999 JCS0682