Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures. Movérare-Skrtic, S., Henning, P., Liu, X., Nagano, K., Saito, H., Börjesson, A. E., Sjögren, K., Windahl, S. H., Farman, H., Kindlund, B., Engdahl, C., Koskela, A., Zhang, F., Eriksson, E. E., Zaman, F., Hammarstedt, A., Isaksson, H., Bally, M., Kassem, A., Lindholm, C., Sandberg, O., Aspenberg, P., Sävendahl, L., Feng, J. Q., Tuckermann, J., Tuukkanen, J., Poutanen, M., Baron, R., Lerner, U. H., Gori, F., & Ohlsson, C. Nature Medicine, 20(11):1279–1288, November, 2014.
doi  abstract   bibtex   
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.
@article{moverare-skrtic_osteoblast-derived_2014,
	title = {Osteoblast-derived {WNT16} represses osteoclastogenesis and prevents cortical bone fragility fractures},
	volume = {20},
	issn = {1546-170X},
	doi = {10.1038/nm.3654},
	abstract = {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.},
	language = {eng},
	number = {11},
	journal = {Nature Medicine},
	author = {Movérare-Skrtic, Sofia and Henning, Petra and Liu, Xianwen and Nagano, Kenichi and Saito, Hiroaki and Börjesson, Anna E. and Sjögren, Klara and Windahl, Sara H. and Farman, Helen and Kindlund, Bert and Engdahl, Cecilia and Koskela, Antti and Zhang, Fu-Ping and Eriksson, Emma E. and Zaman, Farasat and Hammarstedt, Ann and Isaksson, Hanna and Bally, Marta and Kassem, Ali and Lindholm, Catharina and Sandberg, Olof and Aspenberg, Per and Sävendahl, Lars and Feng, Jian Q. and Tuckermann, Jan and Tuukkanen, Juha and Poutanen, Matti and Baron, Roland and Lerner, Ulf H. and Gori, Francesca and Ohlsson, Claes},
	month = nov,
	year = {2014},
	pmid = {25306233},
	pmcid = {PMC4392888},
	keywords = {Aging, Animals, Cell Differentiation, Cell Line, Cell Lineage, Cells, Cultured, Disease Susceptibility, Fractures, Bone, Gene Deletion, Gene Expression Regulation, Humans, Mice, Inbred C57BL, Organ Size, Osteoblasts, Osteoclasts, Osteocytes, Osteogenesis, Osteoprotegerin, RANK Ligand, RNA, Messenger, Signal Transduction, Skull, Wnt Proteins},
	pages = {1279--1288},
}
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