Multiple modes of Lrp4 function in modulation of Wnt/β-catenin signaling during tooth development

Abstract

During development and homeostasis, precise control of Wnt/β-catenin signaling is in part achieved by secreted and membrane proteins that negatively control activity of the Wnt co-receptors Lrp5 and Lrp6. Lrp4 is related to Lrp5/6 and is implicated in modulation of Wnt/β-catenin signaling, presumably through its ability to bind to the Wise (Sostdc1)/sclerostin (Sost) family of Wnt antagonists. To gain insights into the molecular mechanisms of Lrp4 function in modulating Wnt signaling, we performed an array of genetic analyses in murine tooth development, where Lrp4 and Wise play important roles. We provide genetic evidence that Lrp4 mediates the Wnt inhibitory function of Wise and also modulates Wnt/β-catenin signaling independently of Wise. Chimeric receptor analyses raise the possibility that the Lrp4 extracellular domain interacts with Wnt ligands, as well as the Wnt antagonists. Diverse modes of Lrp4 function are supported by severe tooth phenotypes of mice carrying a human mutation known to abolish Lrp4 binding to Sost. Our data suggest a model whereby Lrp4 modulates Wnt/β-catenin signaling via interaction with Wnt ligands and antagonists in a context-dependent manner.

SOST, an LNGFR target, inhibits the osteogenic differentiation of rat ectomesenchymal stem cells

“…Previous studies have revealed that SOST has anti‐anabolic effects on bone formation . Recently, it has been reported that SOST is closely associated with the development of dental tissues . For example, SOST inhibition dramatically stimulates alveolar bone regeneration following experimental periodontitis in Sprague‐Dawley (SD) rats .…”

“…5 Recently, it has been reported that SOST is closely associated with the development of dental tissues. [6][7][8][9] For example, SOST inhibition dramatically stimulates alveolar bone regeneration following experimental periodontitis in Sprague-Dawley (SD) rats. 6 Another report has demonstrated that SOST inhibition resulted in significant new deposition of cellular cementum and the formation of well-organized periodontal ligament fibre in a rat periodontal defect model.…”

Lipid metabolism genes and predisposition to ischemic heart disease

“…Комплекс Wnt посредством аппарата Гольджи секретируется во внекле-точную среду, где он выступает важным участником процесса межклеточной передачи сигналов. Рецепторами Wnt выступают трансмембранные белки Frizzled и рецепторы липопротеинов LRP4, LRP5, LRP6 [41]. Ген локализован на хромосоме 11p11.2.…”

Exercise Promotes the Osteoinduction of HA/β-TCP Biomaterials via the Wnt Signaling Pathway

“…To date, three Wnt signaling pathways have been revealed, including the canonical Wnt/β-catenin pathway, the noncanonical Wnt/Ca 2+ pathway, and the Wnt/planar cell polarity (PCP) pathway [11]. The canonical Wnt/β-catenin pathway plays an important role in the regulation of bone formation and has become a new hotspot in the field of the pathogenesis of skeletal diseases and bone metabolism [12,13]. However, little is known about whether a Wnt/β-catenin signaling pathway could promote ectopic bone formation induced by HA/β-TCP biomaterials through exercise and immunoregulation in mice.…”