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) 1546170x (eISSN)
Vol. 20 11 1279-88Subject Categories
Endocrinology and Diabetes
Clinical Medicine
DOI
10.1038/nm.3654
PubMed
25306233