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

Sofia Movérare-Skrtic ; Petra Henning ; Xianwen Liu ; Kenichi Nagano ; Hiroaki Saito ; Anna E Börjesson ; Klara Sjögren ; Sara H Windahl ; Helen H. Farman ; Bert Kindlund ; Cecilia Engdahl ; Antti Koskela ; Fu-Ping Zhang ; Emma E Eriksson ; Farasat Zaman ; Ann Hammarstedt ; Hanna Isaksson ; Marta Bally (Institutionen för teknisk fysik, Biologisk fysik) ; Ali Kassem ; Catharina Lindholm ; Olof Sandberg ; Per Aspenberg ; Lars Sävendahl ; Jian Q Feng ; Jan Tuckermann ; Juha Tuukkanen ; Matti Poutanen ; Roland Baron ; Ulf H Lerner ; Francesca Gori ; Claes Ohlsson
Nature Medicine (1078-8956). Vol. 20 (2014), 11, p. 1279-88.
[Artikel, refereegranskad vetenskaplig]

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.



Denna post skapades 2014-12-12. Senast ändrad 2015-01-14.
CPL Pubid: 208033

 

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Institutioner (Chalmers)

Institutionen för medicin, avdelningen för invärtesmedicin och klinisk nutrition (GU)
Centre for Bone and Arthritis Research (GU)
Institutionen för medicin (GU)
Institutionen för medicin, avdelningen för reumatologi och inflammationsforskning (GU)
Institutionen för medicin, avdelningen för molekylär och klinisk medicin (GU)
Institutionen för teknisk fysik, Biologisk fysik (2007-2015)

Ämnesområden

Klinisk medicin
Endokrinologi

Chalmers infrastruktur