期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2015
卷号：112
期号：11
页码：3487-3492
DOI：10.1073/pnas.1419714112
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：SignificanceThis study provides in vivo evidence that Lrp4 loss in osteoblast (OB)-lineage cells results in high-bone-mass deficit. Lrp4 in OB-lineage cells is required to reduce serum levels of sclerostin and to facilitate sclerostin inhibition of OB differentiation and function. These results demonstrate that Lrp4 is a critical player in bone-mass homeostasis and support a model that Lrp4 acts as a sclerostin receptor, inhibiting Wnt/{beta}-catenin signaling and promoting receptor activator of nuclear kappa B ligand (RANKL)-induced osteoclastogenesis. As mutations in the Lrp4 gene have been identified in high-bone-mass patients, this study provides pathophysiological insight into relevant high-bone-mass disorders. Bone mass is maintained by balanced activity of osteoblasts and osteoclasts. Lrp4 (low-density lipoprotein receptor related protein 4) is a member of the LDL receptor family, whose mutations have been identified in patients with high-bone-mass disorders, such as sclerosteosis and van Buchem diseases. However, it remains unknown whether and how Lrp4 regulates bone-mass homeostasis in vivo. Here we provide evidence that Lrp4-null mutation or specific mutation in osteoblast-lineage cells increased cortical and trabecular bone mass, which was associated with elevated bone formation and impaired bone resorption. This phenotype was not observed in osteoclast-selective Lrp4 knockout mice. Mechanistic studies indicate that loss of Lrp4 function in osteoblast-lineage cells increased serum levels of sclerostin, a key factor for bone-mass homeostasis that interacts with Lrp4, but abolished the inhibition of Wnt/{beta}-catenin signaling and osteoblastic differentiation by sclerostin. Concomitantly, sclerostin induction of RANKL (receptor activator of nuclear kappa B ligand) was impaired, leading to a lower ratio of RANKL over OPG (osteoprotegerin) (a key factor for osteoclastogenesis). Taken together, these results support the view for Lrp4 as a receptor of sclerostin to inhibit Wnt/{beta}-catenin signaling and bone formation and identify Lrp4 as a critical player in bone-mass homeostasis.
