TY - JOUR
T1 - Lrp4, a novel receptor for dickkopf 1 and sclerostin, is expressed by osteoblasts and regulates bone growth and turnover In Vivo
AU - Choi, Hong Y.
AU - Dieckmann, Marco
AU - Herz, Joachim
AU - Niemeier, Andreas
N1 - Funding Information:
A.N. received a short-term travel grant from Merck, Sharpe and Dohme. This has or had no influence on data collection, experimental planning, data interpretation, decision to publish or time of publication. M.D. is the recipient of a research fellowship from a non-profit foundation (BIS), which takes no influence in data collection, experimental planning, data interpretation, decision to publish or time of publication. H.C. is the recipient of a postdoctoral fellowship from the American Heart Association, which takes no influence data collection, experimental planning, data interpretation, decision to publish or time of publication. J.H. and A.N. are the recipients of grants from National funding agencies in the US (NIH for J.H.) and Germany (DFG for A.N.) respectively. Both funding agencies expect these PIs to publish rapidly and extensively and their ability to do so considerably influences future funding. This may be interpreted as constituting a significant conflict of interest for J.H. and A.N., solely to indicate this fact. No other conflicts of interest exist.
PY - 2009/11/20
Y1 - 2009/11/20
N2 - 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 coreceptors 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.
AB - 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 coreceptors 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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U2 - 10.1371/journal.pone.0007930
DO - 10.1371/journal.pone.0007930
M3 - Article
C2 - 19936252
AN - SCOPUS:70949101564
SN - 1932-6203
VL - 4
JO - PloS one
JF - PloS one
IS - 11
M1 - e7930
ER -