title: Osteoblast-derived WNT16 represses osteoclastogenesis and prevents cortical bone fragility fractures.
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.
authors.affiliation: Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Sofia
authors.initials: S
authors.lastname: Movérare-Skrtic
authors.affiliation: Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Petra
authors.initials: P
authors.lastname: Henning
authors.affiliation: 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.
authors.forename: Xianwen
authors.initials: X
authors.lastname: Liu
authors.affiliation: Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Nagano
authors.affiliation: Department of Oral Medicine, Infection and Immunity, Harvard School of Dental Medicine, Boston, Massachusetts, USA.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Saito
authors.affiliation: Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Anna E
authors.initials: AE
authors.lastname: Börjesson
authors.affiliation: Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Klara
authors.initials: K
authors.lastname: Sjögren
authors.affiliation: Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Sara H
authors.initials: SH
authors.lastname: Windahl
authors.affiliation: Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Helen
authors.initials: H
authors.lastname: Farman
authors.affiliation: Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Bert
authors.initials: B
authors.lastname: Kindlund
authors.affiliation: Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Engdahl
authors.affiliation: Department of Anatomy and Cell Biology, Medical Research Center, University of Oulu, Oulu, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Koskela
authors.affiliation: Turku Center for Disease Modeling, Department of Physiology, Institute of Biomedicine, University of Turku, Turku, Finland.
authors.forename: Fu-Ping
authors.initials: FP
authors.lastname: Zhang
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Pediatric Endocrinology Unit, Stockholm, Sweden.
authors.forename: Emma E
authors.initials: EE
authors.lastname: Eriksson
authors.affiliation: 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.
authors.forename: Farasat
authors.initials: F
authors.lastname: Zaman
authors.affiliation: Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Ann
authors.initials: A
authors.lastname: Hammarstedt
authors.affiliation: 1] Department of Biomedical Engineering, Lund University, Lund, Sweden. [2] Department of Orthopedics, Lund University, Lund, Sweden.
authors.forename: Hanna
authors.initials: H
authors.lastname: Isaksson
authors.affiliation: Department of Applied Physics, Division of Biological Physics, Chalmers University of Technology, Gothenburg, Sweden.
authors.forename: Marta
authors.initials: M
authors.lastname: Bally
authors.affiliation: Molecular Periodontology, Umeå University, Umeå, Sweden.
authors.forename: Ali
authors.identifier: 0000000218208518
authors.initials: A
authors.lastname: Kassem
authors.affiliation: Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Catharina
authors.initials: C
authors.lastname: Lindholm
authors.affiliation: Orthopaedics, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Olof
authors.initials: O
authors.lastname: Sandberg
authors.affiliation: Orthopaedics, Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Aspenberg
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet, Pediatric Endocrinology Unit, Stockholm, Sweden.
authors.forename: Lars
authors.initials: L
authors.lastname: Sävendahl
authors.affiliation: Department of Biomedical Sciences, Baylor College of Dentistry, Texas A&M Health Science Center, Dallas, Texas, USA.
authors.forename: Jian Q
authors.initials: JQ
authors.lastname: Feng
authors.affiliation: Institute of General Zoology and Endocrinology, University of Ulm, Ulm, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Tuckermann
authors.affiliation: Department of Anatomy and Cell Biology, Medical Research Center, University of Oulu, Oulu, Finland.
authors.forename: Juha
authors.initials: J
authors.lastname: Tuukkanen
authors.affiliation: 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.
authors.forename: Matti
authors.initials: M
authors.lastname: Poutanen
authors.affiliation: 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.
authors.forename: Roland
authors.initials: R
authors.lastname: Baron
authors.affiliation: 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.
authors.forename: Ulf H
authors.initials: UH
authors.lastname: Lerner
authors.affiliation: 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.
authors.forename: Francesca
authors.initials: F
authors.lastname: Gori
authors.affiliation: Centre for Bone and Arthritis Research at Institute of Medicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
authors.forename: Claes
authors.initials: C
authors.lastname: Ohlsson
mesh_terms: D000375:Aging / Q000473:pathology; D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D002460:Cell Line; D019070:Cell Lineage / Q000187:drug effects; D002478:Cells, Cultured; D004198:Disease Susceptibility; D050723:Fractures, Bone / Q000235:genetics / Q000378:metabolism* / Q000473:pathology / Q000517:prevention & control*; D017353:Gene Deletion; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects / Q000235:genetics; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010011:Osteocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects / Q000235:genetics; D053244:Osteoprotegerin / Q000378:metabolism; D053245:RANK Ligand / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D012886:Skull / Q000473:pathology; D051153:Wnt Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*
chemical_list: D053244:Osteoprotegerin; D053245:RANK Ligand; D012333:RNA, Messenger; C417262:WNT16 protein, human; D051153:Wnt Proteins; C585687:Wnt16 protein, mouse