Cbfa1-independent decrease in osteoblast proliferation, osteopenia, and persistent embryonic eye vascularization in mice deficient in Lrp5, a Wnt coreceptor

By Masaki Kato, M. Patel, R. Levasseur, I. Lobov, B. Chang, D. Glass, C. Hartmann, Lan Li, T. Hwang, C. Brayton and 3 more. Journal of Cell Biology, 2002

1,131 citations recorded by the source corpus.

The low-density lipoprotein receptor–related protein (Lrp)-5 functions as a Wnt coreceptor. Here we show that mice with a targeted disruption of Lrp5 develop a low bone mass phenotype. In vivo and in vitro analyses indicate that this phenotype becomes evident postnatally, and demonstrate that it is secondary to decreased osteoblast proliferation and function in a Cbfa1-independent manner. Lrp5 is expressed in osteoblasts and is required for optimal Wnt signaling in osteoblasts. In addition, Lrp5-deficient mice display persistent embryonic eye vascularization due to a failure of macrophage-induced endothelial cell apoptosis. These results implicate Wnt proteins in the postnatal control of vascular regression and bone formation, two functions affected in many diseases. Moreover, these features recapitulate human osteoporosis-pseudoglioma syndrome, caused by LRP5 inactivation.

Subfields: Genetics, Molecular Biology

View Paper: https://www.semanticscholar.org/paper/9918a3fc5959c18ccf6a3fa4fbad7e7d92f0808d

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In Genetics

1. Hans Clevers
2. Christof Niehrs
3. Fanxin Long
4. W. Birchmeier
5. D. Ornitz
6. M. Zaidi
7. R. Hen
8. Andrew P. McMahon

In Molecular Biology

1. Hans Clevers
2. Fanxin Long
3. Christof Niehrs
4. Xi He
5. D. Ornitz
6. W. Birchmeier
7. K. Tamai
8. R. Nusse

Citations in the corpus

• Development of the endochondral skeleton. (2013, background): “Conversely, a different set of mutations in Lrp5 that render the coreceptor refractory to extracellular WNT inhibitors DKK1 and Sclerostin (encoded by Sost) cause high-bonemass syndrome (Boyden et al. 2002; Little et al. 2002; Ai et al. 2005; Ellies et al. 2006; Semenov and He 2006).”
• Vascular development in the retina and inner ear: control by Norrin and Frizzled-4, a high-affinity ligand-receptor pair. (2004, neutral): “Ϫ/Ϫ mice (Richter et al., 1998; Kato et al., 2002).”
• Wnt/β-catenin signalling: function, biological mechanisms, and therapeutic opportunities (2022, background): “DKK1 improved NFκB pathway signal transduction, enhanced the inflammatory response at the injury site,255 and promoted ischaemic injury by downregulating LRP5/6.108 The increase in DKK1 in patients was related to the DKK1-mediated inflammation loop.”
• LDL receptor-related proteins 5 and 6 in Wnt/β-catenin signaling: Arrows point the way (2004, background): “LRP5 is required for the proliferation of osteoblasts (Gong et al., 2001; Kato et al., 2002), and may inhibit osteoblast apoptosis (Babij et al., 2003).”
• BMP‐2 Controls Alkaline Phosphatase Expression and Osteoblast Mineralization by a Wnt Autocrine Loop (2003, background): “0 software from Perkin-Elmer: ALP, osteocalcin (OC), collagen type I, Osf2/Cbfa1, PPAR 2, Wnt1, Wnt3a, frizzled1, and frizzled9.”
• Function and biological roles of the Dickkopf family of Wnt modulators (2006, background): “Similar to humans, Lrp5–/– mice have a low bone mass phenotype due to reduced proliferation of precursor cells (Kato et al., 2002), which is enhanced by additional loss of one Lrp6 allele (Holmen et al., 2004).”
• Adult mesenchymal stem cells and cell-based tissue engineering (2002, neutral): “with osteoporosis–pseudoglioma syndrome [69].”
• Canonical Wnt/beta-catenin signaling prevents osteoblasts from differentiating into chondrocytes. (2005, background): “Canonical Wnt/β-catenin signaling has recently been implicated in osteoblastogenesis (Bain et al., 2003; Bodine et al., 2004; Gong et al., 2001; Hartmann and Tabin, 2000; Kato et al., 2002; Rawadi et al., 2003).”
• Conditional inactivation of FGF receptor 2 reveals an essential role for FGF signaling in the regulation of osteoblast function and bone growth (2003, background): “Interestingly, low-density lipoprotein r ceptor-related protein (Lrp)-5-deficient mice have been shown to have a Cbfa1-independent decrease in osteoblast proliferation and bone formation (Kato et al., 2002).”
• Distinct roles for Hedgehog and canonical Wnt signaling in specification, differentiation and maintenance of osteoblast progenitors (2006, result): “These observations have been supported by parallel mouse studies (Kato et al., 2002).”
• Osteoblasts in prostate cancer metastasis to bone (2005, background): “fcgi?db=gene&cmd=Retrieve&dopt=Graphics&list_uids=4041">LRP5 , a WNT co-receptor that regulates bone formation through β-cateni”
• TSH is a negative regulator of skeletal remodeling. (2003, background): “An identical mechanism transduces the antiosteoclastogenic effect of estrogen (Shevde et al., result in osteopenia; in the latter case, Runx-2 expression remains normal (Kato et al., 2002).”
• Sequential roles of Hedgehog and Wnt signaling in osteoblast development (2004, background): “Furthermore, mice deficient in Lrp5 were viable but postnatally developed a low bone mass phenotype because of reduced osteoblast proliferation and function (Kato et al., 2002).”