Lrp5 p. Val667Met Variant Compromises Bone Mineral Density and Matrix Properties in Osteoporosis - Université d'Angers Accéder directement au contenu
Article Dans Une Revue JBMR Plus Année : 2023

Lrp5 p. Val667Met Variant Compromises Bone Mineral Density and Matrix Properties in Osteoporosis

Résumé

Early-onset osteoporosis (EOOP) has been associated with several genes, including LRP5, coding for a coreceptor in the Wnt pathway. Variants in LRP5 were also described in osteoporosis pseudoglioma syndrome, combining severe osteoporosis and eye abnormalities. Genomewide-association studies (GWAS) showed that LRP5 p.Val667Met (V667M) variant is associated with low bone mineral density (BMD) and increased fractures. However, despite association with a bone phenotype in humans and knockout mice, the impact of the variant in bone and eye remains to be investigated. Here, we aimed to evaluate the bone and ocular impact of the V667M variant. We recruited 11 patients carrying the V667M variant or other loss-of-function variants of LRP5 and generated an Lrp5 V667M mutated mice. Patients had low lumbar and hip BMD Z-score and altered bone microarchitecture evaluated by HR-pQCT compared with an agematched reference population. Murine primary osteoblasts from Lrp5 V667M mice showed lower differentiation capacity, alkaline phosphatase activity, and mineralization capacity in vitro. Ex vivo, mRNA expression of Osx, Col1, and osteocalcin was lower in Lrp5 V667M bones than controls (all p < 0.01). Lrp5 V667M 3-month-old mice, compared with control (CTL) mice, had decreased BMD at the femur (p < 0.01) and lumbar spine (p < 0.01) with normal microarchitecture and bone biomarkers. However, Lrp5 V667M mice revealed a trend toward a lower femoral and vertebral stiffness (p = 0.14) and had a lower hydroxyproline/proline ratio compared with CTL, (p = 0.01), showing altered composition and quality of the bone matrix. Finally, higher tortuosity of retinal vessels was found in the Lrp5 V667M mice and unspecific vascular tortuosity in two patients only. In conclusion, Lrp5 V667M variant is associated with low BMD and impaired bone matrix quality. Retinal vascularization abnormalities were observed in mice.
Fichier principal
Vignette du fichier
JBMR Plus - 2023 - Fabre - Lrp5 p Val667Met Variant Compromises Bone Mineral Density and Matrix Properties in Osteoporosis.pdf (3.12 Mo) Télécharger le fichier
Origine : Fichiers éditeurs autorisés sur une archive ouverte
Licence : CC BY - Paternité

Dates et versions

hal-04139607 , version 1 (23-06-2023)

Identifiants

Citer

Stéphanie Fabre, Morgane Bourmaud, Guillaume Mabilleau, Ruben Goulet, Aude Couturier, et al.. Lrp5 p. Val667Met Variant Compromises Bone Mineral Density and Matrix Properties in Osteoporosis. JBMR Plus, 2023, 7 (6), ⟨10.1002/jbm4.10741⟩. ⟨hal-04139607⟩
7 Consultations
14 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More