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Nat Med. 2014 Nov;20(11):1279-88. doi: 10.1038/nm.3654. Epub 2014 Oct 12.

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

Author information

1
Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
2
1] Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA. [2] State Key Laboratory of Oral Diseases and Department of Oral and Maxillofacial Surgery, West China Hospital of Stomatology, Sichuan University, Sichuan, China.
3
Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA.
4
Department of Anatomy and Cell Biology, Medical Research Center, University of Oulu, Oulu, Finland.
5
Turku Center for Disease Modeling, Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland.
6
Department of Women's and Children's Health, Karolinska Institutet, Pediatric Endocrinology Unit, Stockholm, Sweden.
7
1] Department of Women's and Children's Health, Karolinska Institutet, Pediatric Endocrinology Unit, Stockholm, Sweden. [2] Developmental and Stem Cell Biology, the Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada.
8
Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
9
1] Department of Biomedical Engineering, Lund University, Lund, Sweden. [2] Department of Orthopedics, Lund University, Lund, Sweden.
10
Department of Applied Physics, Division of Biological Physics, Chalmers University of Technology, Gothenburg, Sweden.
11
Molecular Periodontology, Umeå University, Umeå, Sweden.
12
Orthopaedics, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
13
Department of Biomedical Sciences, Baylor College of Dentistry, Texas A&M Health Science Center, Dallas, Texas, USA.
14
Institute of General Zoology and Endocrinology, University of Ulm, Ulm, Germany.
15
1] Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. [2] Turku Center for Disease Modeling, Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland.
16
1] Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA. [2] Department of Medicine, Endocrine Unit, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
17
1] Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden. [2] Molecular Periodontology, Umeå University, Umeå, Sweden.

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.

PMID:
25306233
PMCID:
PMC4392888
DOI:
10.1038/nm.3654
[Indexed for MEDLINE]
Free PMC Article

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