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
Harvard University
Southern Medical University
Kenichi Nagano
Harvard University
Hiroaki Saito
Harvard University
Universitatsklinikum Hamburg-Eppendorf und Medizinische Fakultat
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
Turun Yliopisto
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 University
Ulf H Lerner
Göteborgs universitet
Francesca Gori
Massachusetts General Hospital
Harvard University
Claes Ohlsson
Göteborgs universitet
Nature Medicine
1078-8956 (ISSN) 1546170x (eISSN)
Vol. 20 11 1279-88Ämneskategorier (SSIF 2011)
Endokrinologi och diabetes
Klinisk medicin
DOI
10.1038/nm.3654
PubMed
25306233