Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures.
Journal article, 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.

Author

Sofia Movérare-Skrtic

University of Gothenburg

Petra Henning

University of Gothenburg

Xianwen Liu

Harvard School of Dental Medicine

West China Hospital

Southern Medical University

Kenichi Nagano

Harvard School of Dental Medicine

Hiroaki Saito

Universitatsklinikum Hamburg-Eppendorf und Medizinische Fakultat

Harvard School of Dental Medicine

Anna E Börjesson

University of Gothenburg

Klara Sjögren

University of Gothenburg

Sara H Windahl

University of Gothenburg

Helen H. Farman

University of Gothenburg

Bert Kindlund

University of Gothenburg

Cecilia Engdahl

University of Gothenburg

Antti Koskela

University of Oulu

Fu-Ping Zhang

University of Turku

Emma E Eriksson

Karolinska Institutet

Farasat Zaman

Hospital for Sick Children University of Toronto

Karolinska Institutet

Ann Hammarstedt

University of Gothenburg

Hanna Isaksson

Lund University

Marta Bally

Chalmers, Applied Physics, Biological Physics

Ali Kassem

Umeå University

Catharina Lindholm

University of Gothenburg

Olof Sandberg

Linköping University

Per Aspenberg

Linköping University

Lars Sävendahl

Karolinska Institutet

Jian Q Feng

Baylor College of Dentistry

Jan Tuckermann

University of Ulm

Juha Tuukkanen

University of Oulu

Matti Poutanen

University of Gothenburg

Roland Baron

Massachusetts General Hospital

Harvard School of Dental Medicine

Ulf H Lerner

University of Gothenburg

Francesca Gori

Harvard School of Dental Medicine

Massachusetts General Hospital

Claes Ohlsson

University of Gothenburg

Nature Medicine

1078-8956 (ISSN)

Vol. 20 11 1279-88

Subject Categories

Endocrinology and Diabetes

Clinical Medicine

DOI

10.1038/nm.3654

PubMed

25306233

More information

Latest update

8/31/2018