Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures.
Artikel i vetenskaplig tidskrift, 2014

The WNT16 locus is a major determinant of cortical bone thickness and nonvertebral fracture risk in humans. The disability, mortality and costs caused by osteoporosis-induced nonvertebral fractures are enormous. We demonstrate here that Wnt16-deficient mice develop spontaneous fractures as a result of low cortical thickness and high cortical porosity. In contrast, trabecular bone volume is not altered in these mice. Mechanistic studies revealed that WNT16 is osteoblast derived and inhibits human and mouse osteoclastogenesis both directly by acting on osteoclast progenitors and indirectly by increasing expression of osteoprotegerin (Opg) in osteoblasts. The signaling pathway activated by WNT16 in osteoclast progenitors is noncanonical, whereas the pathway activated in osteoblasts is both canonical and noncanonical. Conditional Wnt16 inactivation revealed that osteoblast-lineage cells are the principal source of WNT16, and its targeted deletion in osteoblasts increases fracture susceptibility. Thus, osteoblast-derived WNT16 is a previously unreported key regulator of osteoclastogenesis and fracture susceptibility. These findings open new avenues for the specific prevention or treatment of nonvertebral fractures, a substantial unmet medical need.

Författare

Sofia Movérare-Skrtic

Göteborgs universitet

Petra Henning

Göteborgs universitet

Xianwen Liu

West China Hospital

Southern Medical University

Harvard School of Dental Medicine

Kenichi Nagano

Harvard School of Dental Medicine

Hiroaki Saito

Universitatsklinikum Hamburg-Eppendorf und Medizinische Fakultat

Harvard School of Dental Medicine

Anna E Börjesson

Göteborgs universitet

Klara Sjögren

Göteborgs universitet

Sara H Windahl

Göteborgs universitet

Helen H. Farman

Göteborgs universitet

Bert Kindlund

Göteborgs universitet

Cecilia Engdahl

Göteborgs universitet

Antti Koskela

Oulun Yliopisto

Fu-Ping Zhang

Institute of Biomedicine

Emma E Eriksson

Karolinska Institutet

Farasat Zaman

Karolinska Institutet

Hospital for Sick Children University of Toronto

Ann Hammarstedt

Göteborgs universitet

Hanna Isaksson

Lunds universitet

Marta Bally

Chalmers, Teknisk fysik, Biologisk fysik

Ali Kassem

Umeå universitet

Catharina Lindholm

Göteborgs universitet

Olof Sandberg

Linköpings universitet

Per Aspenberg

Linköpings universitet

Lars Sävendahl

Karolinska Institutet

Jian Q Feng

Baylor College of Dentistry

Jan Tuckermann

Universität Ulm

Juha Tuukkanen

Oulun Yliopisto

Matti Poutanen

Göteborgs universitet

Roland Baron

Massachusetts General Hospital

Harvard School of Dental Medicine

Ulf H Lerner

Göteborgs universitet

Francesca Gori

Harvard School of Dental Medicine

Massachusetts General Hospital

Claes Ohlsson

Göteborgs universitet

Nature Medicine

1078-8956 (ISSN)

Vol. 20 1279-88

Ämneskategorier

Endokrinologi och diabetes

Klinisk medicin

DOI

10.1038/nm.3654

PubMed

25306233