Targeting the LRP5 Pathway Improves Bone Properties in a Mouse Model of Osteogenesis Imperfecta

Jacobsen, Christina M.; Barber, Lauren A.; Ayturk, Ugur M.; Roberts, Heather J.; Deal, Lauren E.; Schwartz, Marissa; Weis, Mary Ann; Eyre, David R.; Zurakowski, David; Robling, Alexander G.; Warman, Matthew L.

doi:10.1002/jbmr.2198

Cited by 78 publications

(101 citation statements)

References 58 publications

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“…The most promising approach to date encompasses neutralizing anti-sclerostin antibodies, the furthest advanced of which was recently demonstrated to increase BMD in postmenopausal osteoporotic women (39). In addition, we and others have recently demonstrated the potential for novel drug-targeting approaches in treating common and rare skeletal disorders such as osteoporosis-pseudoglioma (OPPG), sclerosteosis, and osteogenesis imperfecta (OI) by altering canonical WNT signaling (49)(50)(51)(52). Here, we present a new bone anabolic concept, LRP4 sclerostin facilitator function blocking anti-LRP4 antibodies, which promote bone formation and bone gain in the adult rodent skeleton.…”

Section: Discussionmentioning

confidence: 99%

Disruption of Lrp4 function by genetic deletion or pharmacological blockade increases bone mass and serum sclerostin levels

Chang

Krämer

Huber

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

115

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We identified previously in vitro LRP4 (low-density lipoprotein receptor-related protein 4) as a facilitator of the WNT (Winglesstype) 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.LRP4 | SOST | sclerostin | WNT | bone anabolism

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Section: Discussionmentioning

confidence: 99%

Disruption of Lrp4 function by genetic deletion or pharmacological blockade increases bone mass and serum sclerostin levels

Chang

Krämer

Huber

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

115

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“…Compared with vehi cle treatment, cortical thickness increased as a result of increased bone formation and reduced bone resorp tion 229 . Similar improvements in cortical and trabecu lar bone were observed in Col1a2 +/p.G610C mice treated at 6 weeks of age, and in recessive Crtap −/− mice treated at 1 week or 6 weeks of age 230 . The cortical bone gains in young Brtl/+, Col1a2 +/p.G610C and Crtap −/− mice translated into significant improvements in pre yield measures of bone strength and stiffness [228][229][230] .…”

Section: Emerging Therapeuticsmentioning

confidence: 99%

“…Similar improvements in cortical and trabecu lar bone were observed in Col1a2 +/p.G610C mice treated at 6 weeks of age, and in recessive Crtap −/− mice treated at 1 week or 6 weeks of age 230 . The cortical bone gains in young Brtl/+, Col1a2 +/p.G610C and Crtap −/− mice translated into significant improvements in pre yield measures of bone strength and stiffness [228][229][230] . Although post yield bone brittleness remained unchanged, Raman spectro scopic analyses of bone of age matched controls suggest that anti sclerostin treatment may alleviate the high mineral to matrix ratio in newly formed bone tissue.…”

Section: Emerging Therapeuticsmentioning

confidence: 99%

Osteogenesis imperfecta

Marini

Forlino

Bächinger

et al. 2017

Nat Rev Dis Primers

582

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| Skeletal deformity and bone fragility are the hallmarks of the brittle bone dysplasia osteogenesis imperfecta. The diagnosis of osteogenesis imperfecta usually depends on family history and clinical presentation characterized by a fracture (or fractures) during the prenatal period, at birth or in early childhood; genetic tests can confirm diagnosis. Osteogenesis imperfecta is caused by dominant autosomal mutations in the type I collagen coding genes (COL1A1 and COL1A2) in about 85% of individuals, affecting collagen quantity or structure. In the past decade, (mostly) recessive, dominant and X-linked defects in a wide variety of genes encoding proteins involved in type I collagen synthesis, processing, secretion and post-translational modification, as well as in proteins that regulate the differentiation and activity of bone-forming cells have been shown to cause osteogenesis imperfecta. The large number of causative genes has complicated the classic classification of the disease, and although a new genetic classification system is widely used, it is still debated. Phenotypic manifestations in many organs, in addition to bone, are reported, such as abnormalities in the cardiovascular and pulmonary systems, skin fragility, muscle weakness, hearing loss and dentinogenesis imperfecta. Management involves surgical and medical treatment of skeletal abnormalities, and treatment of other complications. More innovative approaches based on gene and cell therapy, and signalling pathway alterations, are under investigation. NATURE REVIEWS | DISEASE PRIMERS VOLUME 3 | ARTICLE NUMBER 17052 | 1 PRIMER © 2 0 1 7 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d .In this Primer, we provide an overview of epidemio logy, genetics and pathophysiology of osteogenesis imperfecta, as well as diagnosis and management. EpidemiologyStudies from Europe and the United States have found a birth prevalence of osteogenesis imperfecta of 0.3-0.7 per 10,000 births 5,6 . These birth cohort analyses reflect more severe types of osteogenesis imperfecta and do not include more subtle types that become apparent after birth. A population based study that used the Danish National Patient Register found an annual incidence of osteogenesis imperfecta of 1.5 per 10,000 births between 1997 and 2013 (REF. 7). Population surveys in countries with comprehensive medical databases, such as Finland, estimated a prevalence of about 0.5 per 10,000 individ uals 8 , with most having phenotypically milder osteo genesis imperfecta type I and type IV (BOX 1; TABLE 1). Because these birth cohort and population surveys are based on clinical findings and tend to find mutu ally exclusive populations, a reasonable estimate of the incidence of osteogenesis imperfecta is about 1 per 10,000 individuals. Most patients are heterozygous for mutations in COL1A1 or COL1A2. No difference in the prevalence between sexes was reported.Approximately 90% of the 3,000 individuals whose mutations ha...

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“…As such, there is an unmet need of new therapeutic approaches for the treatment of WNT1-related OI and osteoporosis. Sclerostin inhibits WNT signaling by binding to and interfering with WNT ligand engagement with LDL receptor-related protein 5/6 (LRP5/6) (37-39), and has been validated as a potent therapeutic target for increasing bone formation in vivo (48)(49)(50)(51). In fact, anti-sclerostin antibody (Scl-Ab) is currently in phase III clinical trials as an anabolic therapy for postmenopausal osteoporosis (NCT02016716, ClinicalTrials.gov).…”

Section: Introductionmentioning

confidence: 99%