2015
DOI: 10.1371/journal.pone.0140775
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Missense Mutations in LRP5 Associated with High Bone Mass Protect the Mouse Skeleton from Disuse- and Ovariectomy-Induced Osteopenia

Abstract: The low density lipoprotein receptor-related protein-5 (LRP5), a co-receptor in the Wnt signaling pathway, modulates bone mass in humans and in mice. Lrp5 knock-out mice have severely impaired responsiveness to mechanical stimulation whereas Lrp5 gain-of-function knock-in and transgenic mice have enhanced responsiveness to mechanical stimulation. Those observations highlight the importance of Lrp5 protein in bone cell mechanotransduction. It is unclear if and how high bone mass-causing (HBM) point mutations in… Show more

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Cited by 21 publications
(21 citation statements)
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“…Estrogen deficiency also leads (directly or indirectly) to increased RANKL production by a number of cells, or an expansion of cells expressing RANKL, in the bone microenvironment in mouse models (Pacifici 2012), again generally consistent with human studies showing increased RANKL expression on bone marrow stromal cells, T cells, and B cells in estrogen deficient as compared with estrogen-sufficient women (Eghbali-Fatourechi et al 2003). The human studies showing regulation of circulating sclerostin and bone SOST mRNA levels by estrogen (Modder et al 2011a,b; Fujita et al 2014; Farr et al 2015) are also consistent with studies in mice with Lrp5 mutations rendering them resistant to sclerostin (Niziolek et al 2015). These mice have absent or markedly attenuated bone loss following ovariectomy, indicating a potential role for sclerostin in mediating estrogen-deficiency bone loss.…”
Section: Mouse Modelssupporting
confidence: 75%
“…Estrogen deficiency also leads (directly or indirectly) to increased RANKL production by a number of cells, or an expansion of cells expressing RANKL, in the bone microenvironment in mouse models (Pacifici 2012), again generally consistent with human studies showing increased RANKL expression on bone marrow stromal cells, T cells, and B cells in estrogen deficient as compared with estrogen-sufficient women (Eghbali-Fatourechi et al 2003). The human studies showing regulation of circulating sclerostin and bone SOST mRNA levels by estrogen (Modder et al 2011a,b; Fujita et al 2014; Farr et al 2015) are also consistent with studies in mice with Lrp5 mutations rendering them resistant to sclerostin (Niziolek et al 2015). These mice have absent or markedly attenuated bone loss following ovariectomy, indicating a potential role for sclerostin in mediating estrogen-deficiency bone loss.…”
Section: Mouse Modelssupporting
confidence: 75%
“…Specifically, bone formation increases transiently following the initiation of estrogen treatment whereas bone resorption declines; over time, due to the coupling of bone resorption and bone formation [38], bone formation also declines. These correlative human data on a role for sclerostin in mediating estrogen effects on bone turnover are supported by recent studies in mice demonstrating that mice with knock-in mutations of LRP5 causing sclerostin resistance also have attenuated bone loss following ovariectomy [39]. Thus, the hypothesis that inhibition of sclerostin production by estrogen is responsible, at least in part, for estrogen effects on both bone formation and resorption is certainly plausible, but clearly warrants further testing.…”
Section: Hormonal Regulation Of Sclerostinmentioning
confidence: 78%
“…The proteins encoded by these genes form part of a major bone anabolic pathway; variants in genes for other factors interacting with the pathway including WNT3a , DKK1 , and LRP4 have all also been associated with low bone mass and fracture. Variations in LRP5 can cause opposing effects on the bone density of the patient; a loss‐of‐function variant causes osteoporosis‐pseudoglioma (OPPG) (Biha et al, ; Hartikka et al, ; Palsgaard et al, ), whereas a gain‐of‐function variant can cause dramatic increases in bone density (Niziolek et al, ). Confirming the genetic etiology in IJO/childhood‐onset primary osteoporosis is important due to implications for patients' diagnosis and treatment; for the wider family in terms of cascade screening especially in a X‐linked condition, providing accurate information on recurrence risk (as in Patient 1 where there is no risk for his unaffected sons which is reassuring for the family).…”
Section: Discussionmentioning
confidence: 99%