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Bone Abstracts (2016) 5 OC2.1 | DOI: 10.1530/boneabs.5.OC2.1

1Departments of Medical Biochemistry and Genetics, University of Turku, Turku, Finland; 2Department of Endocrinology, Turku University Hospital, Turku, Finland; 3Folkhälsan Institute of Genetics, Helsinki, Finland; 4Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Harvard University, Boston, Massachusetts, USA.

Wnt signaling is a major regulator of bone metabolism. We recently reported that mutations in WNT1 gene in humans cause early onset osteoporosis and severe osteogenesis imperfecta. To identify the cellular source and the mechanisms causing these severe phenotypes we generated and analyzed global and conditional Wnt1 knockout mice.

Heterozygous Wnt1+/− mice were viable and fertile but Wnt1−/− embryos were lost in utero. μCT analysis of tibiae at 12 weeks showed that BV/TV and Tb.N. were significantly decreased in Wnt1+/− male mice compared to controls. We had previously observed Wnt1 expression both in osteocytes and in hematopoietic cells. To bypass the embryonic lethality of Wnt1−/− mice and to identify the major source of Wnt1 in long bones, we targeted Wnt1 knockout to limb bud mesenchymal cells using Prrx1-Cre. All male Wnt1Prrx1−/− mice exhibited spontaneous long bone fractures already by the age of 6 weeks. Trabecular BV/TV was decreased by 70% and Tb.N by 60% in proximal tibia of Wnt1Prrx1−/− mice at 6 weeks by μCT. Significant but smaller reductions were observed at 12 weeks. Cortical thickness was decreased by 47% in Wnt1Prrx1−/− mice in μCT. Histomorphometric analysis at 12 weeks showed significantly increased number of osteoclasts and eroded surface and decreased bone formation, despite unaltered osteoblast number or surface in Wnt1Prrx1−/− mice. Expression of Wnt inhibitor Sclerostin was significantly lower in Wnt1Prrx1−/− long bones. In vitro, Wnt1+/− calvarial cells showed impaired osteoblastic differentiation and bone nodule formation, together with reduced expression of osteoblast marker genes. Interestingly, the expression of OPG, an inhibitor of osteoclast differentiation was decreased in Wnt1+/− calvarial cells suggesting that altered RANKL/OPG ratio could affect the osteoclast phenotype observed in vivo in Wnt1Prrx1−/− mice.

We conclude that mesenchymal cell-derived Wnt1 is an essential regulator of bone metabolism that promotes osteoblast function and inhibits osteoclast differentiation.

Volume 5

43rd Annual European Calcified Tissue Society Congress

Rome, Italy
14 May 2016 - 17 May 2016

European Calcified Tissue Society 

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