Lrp4, a novel receptor for Dickkopf 1 and sclerostin, is expressed by osteoblasts and regulates bone growth and turnover in vivo.
Lrp4, a novel receptor for Dickkopf 1 and sclerostin, is expressed by osteoblasts and regulates bone growth and turnover in vivo.
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DOI：
10.1371/journal.pone.0007930
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发表时间：
2009-11-20
期刊：
影响因子：
3.7
通讯作者：
Niemeier A
中科院分区：
文献类型：
--
作者：
Choi HY;Dieckmann M;Herz J;Niemeier A
Lrp 4是低密度脂蛋白受体基因家族的多功能成员，是发育过程中细胞外信号传导途径的调节剂。例如，Lrp 4结合Wise，一种分泌的Wnt调节剂和BMP拮抗剂。Lrp 4与Lrp 5和Lrp 6共享胞外配体结合结构域内的结构元件，Lrp 5和Lrp 6是两种在骨生成中具有重要作用的已建立的Wnt共受体。硬化蛋白是骨形成的有效骨细胞分泌抑制剂，其直接结合Lrp 5和Lrp 6并调节BMP和Wnt信号传导。sclerostin的抗成骨作用被认为主要是通过成骨细胞内Lrp 5/6抑制Wnt信号传导介导的。Dickkopf 1（Dkk 1）是另一种有效的可溶性Wnt抑制剂，与Lrp 5和Lrp 6结合，可以取代Lrp 5结合的sclerostin，本身受BMP调节。在最近的一项全基因组骨矿物质密度相关研究中，在17 q21的SOST基因附近检测到一个重要的修饰基因座，该基因编码硬化蛋白。此外，LRP 4基因中的非同义SNPs与骨密度相关。在这里，我们表明，Lrp 4在骨和培养的成骨细胞中表达，并在体外结合Dkk 1和sclerostin。Lrp 4缺陷突变小鼠的MicroCT分析显示股骨总长度缩短，股骨皮质周长减少，股骨总骨矿物质含量（BMC）和骨矿物质密度（BMD）降低。腰椎骨小梁体积/总体积（BV/TV）显着减少的突变体和血清和尿骨转换标志物碱性磷酸酶，骨钙素和脱氧吡啶啉增加。我们的结论是，Lrp 4是一种新的成骨细胞表达Dkk 1和sclerostin受体的生理作用，在调节骨生长和营业额，这可能是通过其功能介导的Wnt和BMP信号通路的整合。
Lrp4 is a multifunctional member of the low density lipoprotein-receptor gene family and a modulator of extracellular cell signaling pathways in development. For example, Lrp4 binds Wise, a secreted Wnt modulator and BMP antagonist. Lrp4 shares structural elements within the extracellular ligand binding domain with Lrp5 and Lrp6, two established Wnt co-receptors with important roles in osteogenesis. Sclerostin is a potent osteocyte secreted inhibitor of bone formation that directly binds Lrp5 and Lrp6 and modulates both BMP and Wnt signaling. The anti-osteogenic effect of sclerostin is thought to be mediated mainly by inhibition of Wnt signaling through Lrp5/6 within osteoblasts. Dickkopf1 (Dkk1) is another potent soluble Wnt inhibitor that binds to Lrp5 and Lrp6, can displace Lrp5-bound sclerostin and is itself regulated by BMPs. In a recent genome-wide association study of bone mineral density a significant modifier locus was detected near the SOST gene at 17q21, which encodes sclerostin. In addition, nonsynonymous SNPs in the LRP4 gene were suggestively associated with bone mineral density. Here we show that Lrp4 is expressed in bone and cultured osteoblasts and binds Dkk1 and sclerostin in vitro. MicroCT analysis of Lrp4 deficient mutant mice revealed shortened total femur length, reduced cortical femoral perimeter, and reduced total femur bone mineral content (BMC) and bone mineral density (BMD). Lumbar spine trabecular bone volume per total volume (BV/TV) was significantly reduced in the mutants and the serum and urinary bone turnover markers alkaline phosphatase, osteocalcin and desoxypyridinoline were increased. We conclude that Lrp4 is a novel osteoblast expressed Dkk1 and sclerostin receptor with a physiological role in the regulation of bone growth and turnover, which is likely mediated through its function as an integrator of Wnt and BMP signaling pathways.
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影响因子：
3.7
作者：
Boucher, Philippe;Li, Wei-Ping;Matz, Rachel L.;Takayama, Yoshiharu;Auwerx, Johan;Anderson, Richard G. W.;Herz, Joachim
通讯作者：
Herz, Joachim
DOI：
10.1073/pnas.0503617102
发表时间：
2005-12-13
影响因子：
11.1
作者：
Kobayashi, T;Lyons, KM;Kronenberg, HM
通讯作者：
Kronenberg, HM
影响因子：
11.4
作者：
Grotewold, L;Rüther, U
通讯作者：
Rüther, U
影响因子：
9.8
作者：
Balemans, W;Van Den Ende, J;Van Hul, W
通讯作者：
Van Hul, W
影响因子：
4.2
作者：
Balemans, Wendy;Piters, Elke;Van Hul, Wim
通讯作者：
Van Hul, Wim