Lrp4 in osteoblasts suppresses bone formation and promotes osteoclastogenesis and bone resorption.
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/β-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/β-catenin signaling and bone formation and identify Lrp4 as a critical player in bone-mass homeostasis.
Department of Neuroscience and Regenerative Medicine and Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; Charlie Norwood VA Medical Center, Augusta, GA 30912; and.
Lei
L
Xiong
Department of Neuroscience and Regenerative Medicine and Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912;
Ji-Ung
JU
Jung
Department of Neuroscience and Regenerative Medicine and Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; Department of Neurobiology, Institute of Basic Medical Sciences, Beijing 100850, China.
Haitao
H
Wu
Department of Neuroscience and Regenerative Medicine and Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912;
Wen-Fang
WF
Xia
Department of Neuroscience and Regenerative Medicine and Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912;
Jin-Xiu
JX
Pan
Department of Neuroscience and Regenerative Medicine and Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; Charlie Norwood VA Medical Center, Augusta, GA 30912; and.
Chengyong
C
Shen
Department of Neuroscience and Regenerative Medicine and Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; Charlie Norwood VA Medical Center, Augusta, GA 30912; and wxiong@gru.edu lmei@gru.edu.
Lin
L
Mei
Department of Neuroscience and Regenerative Medicine and Department of Neurology, Medical College of Georgia, Georgia Regents University, Augusta, GA 30912; Charlie Norwood VA Medical Center, Augusta, GA 30912; and wxiong@gru.edu lmei@gru.edu.
Wen-Cheng
WC
Xiong
D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids / Q000097:blood; D000818:Animals; D001854:Bone Marrow Cells / Q000378:metabolism / Q000473:pathology; D001862:Bone Resorption / Q000097:blood / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation; D019070:Cell Lineage; D005269:Femur / Q000000981:diagnostic imaging / Q000473:pathology; D006023:Glycoproteins / Q000097:blood / Q000378:metabolism; D036341:Intercellular Signaling Peptides and Proteins; D026502:LDL-Receptor Related Proteins; D018345:Mice, Knockout; D009132:Muscles / Q000378:metabolism; D009928:Organ Specificity; D010006:Osteoblasts / Q000378:metabolism* / Q000473:pathology; D015675:Osteocalcin / Q000378:metabolism; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D010012:Osteogenesis; D053244:Osteoprotegerin / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency / Q000378:metabolism*; D017154:Stromal Cells / Q000378:metabolism / Q000473:pathology; D060449:Wnt Signaling Pathway; D055114:X-Ray Microtomography; D051176:beta Catenin / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D026502:LDL-Receptor Related Proteins; C116415:Lrp4 protein, mouse; D053244:Osteoprotegerin; D053245:RANK Ligand; D011973:Receptors, LDL; C486030:Sost protein, mouse; D051176:beta Catenin; D015675:Osteocalcin; C036020:deoxypyridinoline
LRP4; osteoblasts; osteoclasts; sclerostin; β-catenin