Identification of a secreted BMP antagonist, ectodin, integrating BMP, FGF, and SHH signals from the tooth enamel knot

Abstract

We have identified mouse and human cDNAs encoding a novel secreted BMP inhibitor, which we have named ectodin. It is most homologous (approximately 37% amino acid identity) to sclerostin that is a secreted BMP antagonist. Recombinant ectodin protein produced in cultured cells was efficiently secreted as a antagonist. Ectodin inhibited the activity of BMP2, BMP4, BMP6, and BMP7 for mouse preosteoblastic MC3T3-E1 cells, and bound to these BMPs with high affinity. Ectodin is intensely expressed in developing ectodermal organs, including teeth, vibrissae, and hair follicles. However, it is absent from the hair placodes and from the enamel knot signaling centers in teeth. In addition, several cell layers surrounding the enamel knots were completely devoid of ectodin transcripts. We analyzed the regulation and function of ectodin in tooth germs. Recombinant ectodin protein antagonized the BMP-mediated induction of Msx2 expression in cultured tooth explants, indicating that ectodin is a secreted BMP inhibitor. BMP2 and BMP7 stimulated ectodin expression in tooth explants, showing that it is part of a feedback mechanism controlling the activity of BMPs. The stimulation of ectodin expression by BMP was prevented by SHH and FGF4 but not by Wnt6. Hence, the feedback mechanism whereby BMPs upregulate their own inhibitor is counteracted by signals coexpressed with BMPs in the enamel knot. We conclude that ectodin is a novel BMP inhibitor which integrates BMP signaling with the SHH and FGF signal pathways and contributes in defining the exact spatiotemporal domain of BMP target field around the ectodermal signaling centers.

Modulation of activin/bone morphogenetic protein signaling by follistatin is required for the morphogenesis of mouse molar teeth

“…It is interesting to note that the expression of follistatin is complementary to ectodin, a recently identified BMP inhibitor that is down-regulated in the enamel knot and surrounding tissue (Laurikkala et al, 2003). The inhibition of ectodin expression was regulated by Shh and FGF, presumably from the enamel knot.…”

“…Misregulation of TGF␤ signaling often results in congenital defects as well as cancer and other diseases (Chang et al, 2002;Gumienny and Padgett, 2002). The extracellular inhibitors of BMPs include noggin, chordin, DAN/Cerberus, sclerostin, ectodin and follistatin (Balemans and Van Hul, 2002;Laurikkala et al, 2003). Follistatin is a secreted protein that was originally identified as an activin-antagonizing protein (Nakamura et al, 1990).…”

A Human Bone Morphogenetic Protein Antagonist Is Down-Regulated in Renal Cancer

“…In other species, this protein is known as USAG-1 (Rattus norvegius; Yanagita et al, 2004), ectodin (Mus musculus; Laurikkala et al, 2003;Kassai et al, 2005), and wise (Xenopus laevis; Itasaki et al, 2003). Recent mouse knockouts of ectodin/USAG-1 have shown that this molecule is important in tooth formation and modulation of the renoprotective effects of BMP-7 (Kassai et al, 2005;.…”

Sclerostin: A gem from the genome leads to bone-building antibodies

“…The Xenopus publication described a context-dependent activator and inhibitor of Wnt signaling (given the name Wise) that acted by binding to LRP6, a protein closely related to LRP5. (29) Wise, also known as ectodin, (30) USAG-1, (31) and SOSTDC1, is most closely related to sclerostin, and together they make up the two-member sclerostin family. These interesting findings in Xenopus, coupled with the sclerostin and LRP5 genetic data, strongly suggested that sclerostin acted at the molecular level, at least in part, by binding to LRP5.…”