title: Disruption of Lrp4 function by genetic deletion or pharmacological blockade increases bone mass and serum sclerostin levels.
abstract: We identified previously in vitro LRP4 (low-density lipoprotein receptor-related protein 4) as a facilitator of the WNT (Wingless-type) antagonist sclerostin and found mutations disrupting this function to be associated with high bone mass in humans similar to patients lacking sclerostin. To further delineate the role of LRP4 in bone in vivo, we generated mice lacking Lrp4 in osteoblasts/osteocytes or osteocytes only. Lrp4 deficiency promoted progressive cancellous and cortical bone gain in both mutants, although more pronouncedly in mice deficient in osteoblast/osteocyte Lrp4, consistent with our observation in human bone that LRP4 is most strongly expressed by osteoblasts and early osteocytes. Bone gain was related primarily to increased bone formation. Interestingly, Lrp4 deficiency in bone dramatically elevated serum sclerostin levels whereas bone expression of Sost encoding for sclerostin was unaltered, indicating that osteoblastic Lrp4 retains sclerostin within bone. Moreover, we generated anti-LRP4 antibodies selectively blocking sclerostin facilitator function while leaving unperturbed LRP4-agrin interaction, which is essential for neuromuscular junction function. These antibodies increased bone formation and thus cancellous and cortical bone mass in skeletally mature rodents. Together, we demonstrate a pivotal role of LRP4 in bone homeostasis by retaining and facilitating sclerostin action locally and provide a novel avenue to bone anabolic therapy by antagonizing LRP4 sclerostin facilitator function.
authors.affiliation: Musculoskeletal Disease Area.
authors.forename: Ming-Kang
authors.initials: MK
authors.lastname: Chang
authors.affiliation: Musculoskeletal Disease Area.
authors.forename: Ina
authors.initials: I
authors.lastname: Kramer
authors.affiliation: Biologics, and.
authors.forename: Thomas
authors.initials: T
authors.lastname: Huber
authors.affiliation: Developmental and Molecular Pathways, Novartis Institutes for BioMedical Research, CH-4002 Basel, Switzerland.
authors.forename: Bernd
authors.initials: B
authors.lastname: Kinzel
authors.affiliation: Musculoskeletal Disease Area.
authors.forename: Sabine
authors.initials: S
authors.lastname: Guth-Gundel
authors.affiliation: Musculoskeletal Disease Area.
authors.forename: Olivier
authors.initials: O
authors.lastname: Leupin
authors.affiliation: Musculoskeletal Disease Area, michaela.kneissel@novartis.com.
authors.forename: Michaela
authors.initials: M
authors.lastname: Kneissel
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000368:Aged; D018171:Agrin / Q000378:metabolism; D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D015519:Bone Density; D001842:Bone and Bones / Q000378:metabolism*; D002460:Cell Line; D005260:Female; D005272:Femur Neck / Q000382:microbiology; D015870:Gene Expression; D006023:Glycoproteins / Q000097:blood* / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D026502:LDL-Receptor Related Proteins; D008297:Male; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D009469:Neuromuscular Junction / Q000378:metabolism; D010006:Osteoblasts / Q000378:metabolism; D010011:Osteocytes / Q000378:metabolism; D010012:Osteogenesis / Q000235:genetics; D011485:Protein Binding; D017208:Rats, Wistar; D011973:Receptors, LDL / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055114:X-Ray Microtomography
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D018171:Agrin; D019138:Antibodies, Blocking; D006023:Glycoproteins; D036341:Intercellular Signaling Peptides and Proteins; D026502:LDL-Receptor Related Proteins; C116415:Lrp4 protein, mouse; D011973:Receptors, LDL; C486030:Sost protein, mouse
keywords: LRP4; SOST; WNT; bone anabolism; sclerostin