Levels of serotonin, sclerostin, bone turnover markers as well as bone density and microarchitecture in patients with high-bone-mass phenotype due to a mutation in Lrp5

Frost, Morten; Andersen, T.; Gossiel, Fatma; Hansen, Stinus; Bollerslev, Jens; Hul, Wim Van; Eastell, Richard; Kassem, Moustapha; Brixen, Kim

doi:10.1002/jbmr.376

Cited by 70 publications

(64 citation statements)

References 36 publications

(68 reference statements)

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“…Although we confirmed the biochemical findings recently (21,40), these findings have never been established in other HBM cohorts, as systematic bone metabolic studies have not been published.…”

Section: Evidence For a Role Of Canonical Wnt Signaling In Bone Resorsupporting

confidence: 78%

“…In all patients, clinical symptoms progressed, whereas the carrier remained asymptomatic (20). The progression of symptoms is in alignment with progression of the universal osteosclerosis, as indicated by cross-sectional studies using DXA and histomorphometry (11,12,20,21,23).…”

Section: Summary Of Recent Systematic Clinical Studiesmentioning

confidence: 60%

“…Moreover, Frost et al (21) recently updated the HBM T253I cohort. Bone mass in adults based on dual-energy X-ray absorptiometry (DXA) is almost increased to the same level in patients with the boneresorptive defect (ADO) as in patients with LRP5 activation bone disease.…”

Section: Summary Of Recent Systematic Clinical Studiesmentioning

confidence: 99%

“…Z-scores ranged from C2 to C12 at the lumbar spine, which is mostly comprised of trabecular bone, and the whole-body compartment, consisting primarily of cortical bone, Fig. 1, also illustrating studies by high-resolution peripheral quantitative computed tomography (CT) (20,21,22).…”

Section: Summary Of Recent Systematic Clinical Studiesmentioning

confidence: 99%

“…It is at present unknown whether manipulating sclerostin levels will have unintended effects on the neuromuscular response as seen in humans in relation to unloading (165). Moreover, some of the HBM mutations appear to prevent sclerostin by itself from binding to LRP5 (122), possibly explaining the increased level of sclerostin observed in patients with HBM (21).…”

Section: Treatment Of Hbmmentioning

confidence: 99%

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Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Bollerslev

Henriksen

Nielsen

et al. 2013

European Journal of Endocrinology

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Systematic studies of autosomal dominant osteopetrosis (ADO) were followed by the identification of underlying mutations giving unique possibilities to perform translational studies. What was previously designated ADO1 turned out to be a high bone mass phenotype caused by a missense mutation in the first propeller of LRP5, a region of importance for binding inhibitory proteins. Thereby, ADO1 cannot be regarded as a classical form of osteopetrosis but must now be considered a disease of LRP5 activation. ADO (Albers-Schönberg disease, or previously ADO2) is characterized by increased number of osteoclasts and a defect in the chloride transport system (ClC-7) of importance for acidification of the resorption lacuna (a form of Chloride Channel 7 Deficiency Osteopetrosis). Ex vivo studies of osteoclasts from ADO have shown that cells do form normally but have reduced resorption capacity and an expanded life span. Bone formation seems normal despite decreased osteoclast function. Uncoupling of formation from resorption makes ADO of interest for new strategies for treatment of osteoporosis. Recent studies have integrated bone metabolism in whole-body energy homeostasis. Patients with ADO may have decreased insulin levels indicating importance beyond bone metabolism. There seems to be a paradigm shift in the treatment of osteoporosis. Targeting ClC-7 might introduce a new principle of dual action. Drugs affecting ClC-7 could be antiresorptive, still allowing ongoing bone formation. Inversely, drugs affecting the inhibitory site of LRP5 might stimulate bone formation and inhibit resorption. Thereby, these studies have highlighted several intriguing treatment possibilities, employing novel modes of action, which could provide benefits to the treatment of osteoporosis.

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Section: Evidence For a Role Of Canonical Wnt Signaling In Bone Resorsupporting

confidence: 78%

Section: Summary Of Recent Systematic Clinical Studiesmentioning

confidence: 60%

Section: Summary Of Recent Systematic Clinical Studiesmentioning

confidence: 99%

Section: Summary Of Recent Systematic Clinical Studiesmentioning

confidence: 99%

Section: Treatment Of Hbmmentioning

confidence: 99%

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Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Bollerslev

Henriksen

Nielsen

et al. 2013

European Journal of Endocrinology

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Development of the Bone Phenotype and microRNA Profile in Adults With Low‐Density Lipoprotein Receptor‐Related Protein 5–High Bone Mass (LRP5‐HBM) Disease

Lauterlein

Gossiel

Weigl³

et al. 2021

JBMR Plus

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LRP6 High Bone Mass Characterized in Two Generations Harboring a Unique Mutation of Low‐Density Lipoprotein Receptor‐Related Protein 6

et al. 2023

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Osteoblast Wnt/ β ‐catenin signaling conditions skeletal development and health. Bone formation is stimulated when on the osteoblast surface a Wnt binds to low‐density lipoprotein receptor‐related protein 5 (LRP5) or 6 (LRP6), in turn coupled to a frizzled receptor. Sclerostin and dickkopf1 inhibit osteogenesis if either links selectively to the first β‐propeller of LRP5 or LRP6, thereby disassociating these cognate co‐receptors from the frizzled receptor. Sixteen heterozygous mutations identified since 2002 within LRP5 and three heterozygous mutations identified since 2019 within LRP6 prevent this binding of sclerostin or dickkopf1 and account for the exceptionally rare, but highly instructive, autosomal dominant disorders called LRP5 and LRP6 high bone mass (HBM). Herein, we characterize LRP6 HBM in the first large affected family. Their novel heterozygous LRP6 missense mutation (c.719C>T, p.Thr240Ile) was present in two middle‐aged sisters and three of their sons. They considered themselves healthy. Their broad jaw and torus palatinus developed during childhood and, contrary to the two previous reports of LRP6 HBM, the appearance of their adult dentition was unremarkable. Skeletal modeling, defined radiographically, supported classification as an endosteal hyperostosis. Areal bone mineral density (g/cm 2 ) of the lumbar spine and total hip featured accelerated increases reaching Z ‐scores of ~ +8 and +6, respectively, although biochemical markers of bone formation were normal. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

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Levels of serotonin, sclerostin, bone turnover markers as well as bone density and microarchitecture in patients with high-bone-mass phenotype due to a mutation in Lrp5

Cited by 70 publications

References 36 publications

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Genetics in Endocrinology: Autosomal dominant osteopetrosis revisited: lessons from recent studies

Development of the Bone Phenotype and microRNA Profile in Adults With Low‐Density Lipoprotein Receptor‐Related Protein 5–High Bone Mass (LRP5‐HBM) Disease

LRP6 High Bone Mass Characterized in Two Generations Harboring a Unique Mutation of Low‐Density Lipoprotein Receptor‐Related Protein 6

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