Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fracture

Sofia Movérare-Skrtic, Petra Henning, Xianwen Liu, Kenichi Nagano, Hiroaki Saito, Anna Borjesson, Klara Sjogren, Sara H Windahl, Helen H Farman, Kindlund Bert, Cecilia Engdahl, Antti Koskela, Fu-Ping zhang, Emma Eriksson, Farasat Zaman, Ann Hammarstedt, Isaksson Hanna, Bally Marta, Ali Kassem, Lindholm CatharinaSandberg Olof, Aspenberg Per, Lars Savendahl, Jian Q Feng, Tuckerman Jan, Juha Tuukkanen, Matti Poutanen, Roland Baron, Ulf H Lerner, Francesca Gori, Claes Ohlsson

Research output: Contribution to journalArticlepeer-review

Abstract / Description of output

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.
Original languageEnglish
Pages (from-to)1279-1288
Number of pages10
JournalNature Medicine
Volume20
Issue number11
Early online date12 Oct 2014
DOIs
Publication statusPublished - Nov 2014

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