<i>Lrp6</i> Hypomorphic Mutation Affects Bone Mass Through Bone Resorption in Mice and Impairs Interaction With Mesd

Kubota, Takuo; Michigami, Toshimi; Sakaguchi, Nobuki; Kokubu, Chikara; Suzuki, Akira; Namba, Noriyuki; Sakai, Norio; Nakajima, Shigeo; Imai, Kenji; Ozono, Keiichi

doi:10.1359/jbmr.080512

Cited by 67 publications

(58 citation statements)

References 37 publications

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“…In addition, several LRP5 mutations associated with high bone density syndromes and previously shown to prevent Dkk from binding to LRP5 are located in the first BP domain (33) rather than domain 3 or 4. This suggests that BP34 may not be the only site for Dkk1 binding on LRP5, and this possibility was confirmed by the observation that Dkk1 can also bind to the BP12 of LRP5 (34), and probably to LRP6 as well, because LRP6 is also involved in bone metabolism (7). In the present study, we demonstrated that LRP6 BP12 and BP34 are functional units displaying different ligand binding preferences.…”

Section: Two Independent Folding and Ligand-binding Domains Of Lrp6supporting

confidence: 66%

Cooperative Folding and Ligand-binding Properties of LRP6 β-Propeller Domains

Liu

Pearson

2009

Journal of Biological Chemistry

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Wnt/␤-catenin signaling controls cell growth during development, and its misregulation in adults can cause human diseases. LRP6, the essential co-receptor for the Wnt pathway, consists of four ␤-propeller domains flanked by epidermal growth factor repeats in its extracellular region. To understand the maturation and ligand-binding properties of individual BP domains, we generated soluble receptor consisting of individual BPs, as well as combinations of these domains. We show that BP1, BP2, and BP4 each can be folded and secreted, and their secretion was enhanced by co-expression of Mesd, a molecular chaperone essential for LRP6 folding and maturation. BP3 is not secreted when expressed on its own or in combination with BP2 or BP1 and 2 (BP12); however, folding and secretion of BP3 is vastly enhanced when expressed together with BP4. Similar cooperative folding and maturation was observed between BP1 and BP2. These results suggest that BP1 forms a functional folding unit with BP2, whereas BP3 folds together with BP4. Using these BP constructs, we also found that BP12 and BP34 constitute independent ligand-binding domains capable of binding Wnt3a, Dkk1, and Mesd. The ability of Mesd to block the binding of both Wnt3a and Dkk1 to LRP6 enables this specialized chaperone to function as a Wnt signaling modulator. Together, our studies reveal unique properties of the LRP6 BP domains and provide novel tools to understand LRP6 function in ligand binding and Wnt signaling. Our results also support the development of soluble LRP6 receptors and Mesd as potential therapeutic molecules that target Wnt signaling.

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Section: Two Independent Folding and Ligand-binding Domains Of Lrp6supporting

confidence: 66%

Cooperative Folding and Ligand-binding Properties of LRP6 β-Propeller Domains

Liu

Pearson

2009

Journal of Biological Chemistry

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“…Canonical Wnt signals promote initiation of the former 17 and inhibit bone resorption 30 , while noncanonical Wnt signals promote mature tissue calcification via both mechanisms 31, 32 . LRP6 can restrain noncanonical signals in part by sequestering certain Fzd co-receptors 15 .…”

Section: Resultsmentioning

confidence: 99%

Vascular Smooth Muscle LRP6 Limits Arteriosclerotic Calcification in Diabetic LDLR ^−/− Mice by Restraining Noncanonical Wnt Signals

Cheng

Ramachandran

Behrmann

et al. 2015

Circulation Research

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Rationale Wnt signaling regulates key aspects of diabetic vascular disease. Objective We generated SM22-Cre;LRP6(fl/fl);LDLR-/- mice to determine contributions of Wnt co-receptor LRP6 in the vascular smooth muscle lineage (VSM) of male LDLR-null mice, a background susceptible to diet (HFD) - induced diabetic arteriosclerosis. Methods and Results As compared to LRP6(fl/fl);LDLR-/- controls, SM22-Cre;LRP6(fl/fl);LDLR-/- (LRP6-VKO) siblings exhibited increased aortic calcification on HFD without changes in fasting glucose, lipids, or body composition. Pulse wave velocity (index of arterial stiffness) was also increased. Vascular calcification paralleled enhanced aortic osteochondrogenic programs and circulating osteopontin (OPN), a matricellular regulator of arteriosclerosis. Survey of ligands and Frizzled (Fzd) receptor profiles in LRP6-VKO revealed upregulation of canonical and noncanonical Wnts alongside Fzd10. Fzd10 stimulated noncanonical signaling and OPN promoter activity via an USF-activated cognate inhibited by LRP6. RNAi revealed that USF1 but not USF2 supports OPN expression in LRP6-VKO VSM, and immunoprecipitation confirmed increased USF1 association with OPN chromatin. ML141, an antagonist of cdc42/Rac1 noncanonical signaling, inhibited USF1 activation, osteochondrogenic programs, alkaline phosphatase, and VSM calcification. Mass spectrometry identified LRP6 binding to protein arginine methyltransferase (PRMT) - 1, and nuclear asymmetric dimethylarginine modification was increased with LRP6-VKO. RNAi demonstrated that PRMT1 inhibits OPN and TNAP while PRMT4 supports expression. USF1 complexes containing the H3R17Me2a signature of PRMT4 are increased with LRP6-VKO. Jmjd6, a demethylase downregulated with LRP6 deficiency, inhibits OPN and TNAP expression, USF1:H3R17Me2a complex formation and transactivation. Conclusions LRP6 restrains VSM noncanonical signals that promote osteochondrogenic differentiation, mediated in part via USF1- and arginine methylation – dependent relays.

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“…Similarly, a spontaneous missense mutation of LRP6 in mice (named ringelswanz) was also discovered to affect development and osteogenic homeostasis. Mice homozygous for ringelswanz showed skeletal abnormalities, delayed ossification during development [Kokubu et al 2004] and low bone density as adults due to reduced canonical Wnt signaling [Kubota et al 2008]. Lastly, LRP6 deletion was shown to disrupt bone density synergistically with LRP5 deletion during the osteogenic development of mice, illustrating the critical interplay between LRP6 and LRP5 in skeletal development and bone formation [Holmen et al 2004].…”

Section: Extracellular Components Of the Wnt Signaling Pathway In Ostmentioning

confidence: 96%

Wnt signaling in bone formation and its therapeutic potential for bone diseases

Kim

Liu

Wang

et al. 2013

Therapeutic Advances in Musculoskeletal

284

239

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Abstract:The Wnt signaling pathway plays an important role not only in embryonic development but also in the maintenance and differentiation of the stem cells in adulthood. In particular, Wnt signaling has been shown as an important regulatory pathway in the osteogenic differentiation of mesenchymal stem cells. Induction of the Wnt signaling pathway promotes bone formation while inactivation of the pathway leads to osteopenic states. Our current understanding of Wnt signaling in osteogenesis elucidates the molecular mechanisms of classic osteogenic pathologies. Activating and inactivating aberrations of the canonical Wnt signaling pathway in osteogenesis results in sclerosteosis and osteoporosis respectively. Recent studies have sought to target the Wnt signaling pathway to treat osteogenic disorders. Potential therapeutic approaches attempt to stimulate the Wnt signaling pathway by upregulating the intracellular mediators of the Wnt signaling cascade and inhibiting the endogenous antagonists of the pathway. Antibodies against endogenous antagonists, such as sclerostin and dickkopf-1, have demonstrated promising results in promoting bone formation and fracture healing. Lithium, an inhibitor of glycogen synthase kinase 3β, has also been reported to stimulate osteogenesis by stabilizing β catenin. Although manipulating the Wnt signaling pathway has abundant therapeutic potential, it requires cautious approach due to risks of tumorigenesis. The present review discusses the role of the Wnt signaling pathway in osteogenesis and examines its targeted therapeutic potential.

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Lrp6 Hypomorphic Mutation Affects Bone Mass Through Bone Resorption in Mice and Impairs Interaction With Mesd

Cited by 67 publications

References 37 publications

Cooperative Folding and Ligand-binding Properties of LRP6 β-Propeller Domains

Cooperative Folding and Ligand-binding Properties of LRP6 β-Propeller Domains

Vascular Smooth Muscle LRP6 Limits Arteriosclerotic Calcification in Diabetic LDLR ^−/− Mice by Restraining Noncanonical Wnt Signals

Wnt signaling in bone formation and its therapeutic potential for bone diseases

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Lrp6 Hypomorphic Mutation Affects Bone Mass Through Bone Resorption in Mice and Impairs Interaction With Mesd

Cited by 67 publications

References 37 publications

Cooperative Folding and Ligand-binding Properties of LRP6 β-Propeller Domains

Cooperative Folding and Ligand-binding Properties of LRP6 β-Propeller Domains

Vascular Smooth Muscle LRP6 Limits Arteriosclerotic Calcification in Diabetic LDLR −/− Mice by Restraining Noncanonical Wnt Signals

Wnt signaling in bone formation and its therapeutic potential for bone diseases

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Vascular Smooth Muscle LRP6 Limits Arteriosclerotic Calcification in Diabetic LDLR ^−/− Mice by Restraining Noncanonical Wnt Signals