Anti–USAG-1 therapy for tooth regeneration through enhanced BMP signaling

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2024-12-14 00:00:11

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Uterine sensitization–associated gene-1 (USAG-1) deficiency leads to enhanced bone morphogenetic protein (BMP) signaling, leading to supernumerary teeth formation. Furthermore, antibodies interfering with binding of USAG-1 to BMP, but not lipoprotein receptor–related protein 5/6 (LRP5/6), accelerate tooth development. Since USAG-1 inhibits Wnt and BMP signals, the essential factors for tooth development, via direct binding to BMP and Wnt coreceptor LRP5/6, we hypothesized that USAG-1 plays key regulatory roles in suppressing tooth development. However, the involvement of USAG-1 in various types of congenital tooth agenesis remains unknown. Here, we show that blocking USAG-1 function through USAG-1 knockout or anti–USAG-1 antibody administration relieves congenital tooth agenesis caused by various genetic abnormalities in mice. Our results demonstrate that USAG-1 controls the number of teeth by inhibiting development of potential tooth germs in wild-type or mutant mice missing teeth. Anti–USAG-1 antibody administration is, therefore, a promising approach for tooth regeneration therapy.

Like beaks, nails, horns, and several eccrine glands, teeth are ectodermal organs. Tooth morphogenesis is regulated by a signal transduction network involving interactions between the epithelium and mesenchyme (1–3). Interactions involving positive and negative loops among bone morphogenetic protein (BMP), fibroblast growth factors, Sonic hedgehog, and Wnt pathways regulate the morphogenesis of individual teeth (1, 4). While the number of teeth is usually strictly controlled in individual species (5), it can increase or decrease congenitally in about 1% of individuals (6–8). Conditions of decreases and increases in the usual number of teeth are called tooth agenesis and supernumerary teeth, respectively. Analyses of mouse models have begun to clarify the genetic factors and molecular and pathological mechanisms underlying these conditions (4, 9).