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The Wnt Serpentine Receptor Frizzled-9 Regulates New Bone Formation in Fracture Healing
Wnt signaling is a key regulator of bone metabolism and fracture healing. The canonical Wnt/β-catenin pathway is regarded as the dominant mechanism, and targeting this pathway has emerged as a promising strategy for the treatment of osteoporosis and poorly healing fractures. In contrast, little is k...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Public Library of Science
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877253/ https://www.ncbi.nlm.nih.gov/pubmed/24391920 http://dx.doi.org/10.1371/journal.pone.0084232 |
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author | Heilmann, Aline Schinke, Thorsten Bindl, Ronny Wehner, Tim Rapp, Anna Haffner-Luntzer, Melanie Nemitz, Claudia Liedert, Astrid Amling, Michael Ignatius, Anita |
author_facet | Heilmann, Aline Schinke, Thorsten Bindl, Ronny Wehner, Tim Rapp, Anna Haffner-Luntzer, Melanie Nemitz, Claudia Liedert, Astrid Amling, Michael Ignatius, Anita |
author_sort | Heilmann, Aline |
collection | PubMed |
description | Wnt signaling is a key regulator of bone metabolism and fracture healing. The canonical Wnt/β-catenin pathway is regarded as the dominant mechanism, and targeting this pathway has emerged as a promising strategy for the treatment of osteoporosis and poorly healing fractures. In contrast, little is known about the role of non-canonical Wnt signaling in bone. Recently, it was demonstrated that the serpentine receptor Fzd9, a Wnt receptor of the Frizzled family, is essential for osteoblast function and positively regulates bone remodeling via the non-canonical Wnt pathway without involving β-catenin-dependent signaling. Here we investigated whether the Fzd9 receptor is essential for fracture healing using a femur osteotomy model in Fzd9 (−/−) mice. After 10, 24 and 32 days the fracture calli were analyzed using biomechanical testing, histomorphometry, immunohistochemistry, and micro-computed tomography. Our results demonstrated significantly reduced amounts of newly formed bone at all investigated healing time points in the absence of Fzd9 and, accordingly, a decreased mechanical competence of the callus tissue in the late phase of fracture healing. In contrast, cartilage formation and numbers of osteoclasts degrading mineralized matrix were unaltered. β-Catenin immunolocalization showed that canonical Wnt-signaling was not affected in the absence of Fzd9 in osteoblasts as well as in proliferating and mature chondrocytes within the fracture callus. The expression of established differentiation markers was not altered in the absence of Fzd9, whereas chemokines Ccl2 and Cxcl5 seemed to be reduced. Collectively, our results suggest that non-canonical signaling via the Fzd9 receptor positively regulates intramembranous and endochondral bone formation during fracture healing, whereas it does not participate in the formation of cartilage or in the osteoclastic degradation of mineralized matrix. The finding that Fzd9, in addition to its role in physiological bone remodeling, regulates bone repair may have implications for the development of treatments for poorly or non-healing fractures. |
format | Online Article Text |
id | pubmed-3877253 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-38772532014-01-03 The Wnt Serpentine Receptor Frizzled-9 Regulates New Bone Formation in Fracture Healing Heilmann, Aline Schinke, Thorsten Bindl, Ronny Wehner, Tim Rapp, Anna Haffner-Luntzer, Melanie Nemitz, Claudia Liedert, Astrid Amling, Michael Ignatius, Anita PLoS One Research Article Wnt signaling is a key regulator of bone metabolism and fracture healing. The canonical Wnt/β-catenin pathway is regarded as the dominant mechanism, and targeting this pathway has emerged as a promising strategy for the treatment of osteoporosis and poorly healing fractures. In contrast, little is known about the role of non-canonical Wnt signaling in bone. Recently, it was demonstrated that the serpentine receptor Fzd9, a Wnt receptor of the Frizzled family, is essential for osteoblast function and positively regulates bone remodeling via the non-canonical Wnt pathway without involving β-catenin-dependent signaling. Here we investigated whether the Fzd9 receptor is essential for fracture healing using a femur osteotomy model in Fzd9 (−/−) mice. After 10, 24 and 32 days the fracture calli were analyzed using biomechanical testing, histomorphometry, immunohistochemistry, and micro-computed tomography. Our results demonstrated significantly reduced amounts of newly formed bone at all investigated healing time points in the absence of Fzd9 and, accordingly, a decreased mechanical competence of the callus tissue in the late phase of fracture healing. In contrast, cartilage formation and numbers of osteoclasts degrading mineralized matrix were unaltered. β-Catenin immunolocalization showed that canonical Wnt-signaling was not affected in the absence of Fzd9 in osteoblasts as well as in proliferating and mature chondrocytes within the fracture callus. The expression of established differentiation markers was not altered in the absence of Fzd9, whereas chemokines Ccl2 and Cxcl5 seemed to be reduced. Collectively, our results suggest that non-canonical signaling via the Fzd9 receptor positively regulates intramembranous and endochondral bone formation during fracture healing, whereas it does not participate in the formation of cartilage or in the osteoclastic degradation of mineralized matrix. The finding that Fzd9, in addition to its role in physiological bone remodeling, regulates bone repair may have implications for the development of treatments for poorly or non-healing fractures. Public Library of Science 2013-12-31 /pmc/articles/PMC3877253/ /pubmed/24391920 http://dx.doi.org/10.1371/journal.pone.0084232 Text en © 2013 Heilmann et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Heilmann, Aline Schinke, Thorsten Bindl, Ronny Wehner, Tim Rapp, Anna Haffner-Luntzer, Melanie Nemitz, Claudia Liedert, Astrid Amling, Michael Ignatius, Anita The Wnt Serpentine Receptor Frizzled-9 Regulates New Bone Formation in Fracture Healing |
title | The Wnt Serpentine Receptor Frizzled-9 Regulates New Bone Formation in Fracture Healing |
title_full | The Wnt Serpentine Receptor Frizzled-9 Regulates New Bone Formation in Fracture Healing |
title_fullStr | The Wnt Serpentine Receptor Frizzled-9 Regulates New Bone Formation in Fracture Healing |
title_full_unstemmed | The Wnt Serpentine Receptor Frizzled-9 Regulates New Bone Formation in Fracture Healing |
title_short | The Wnt Serpentine Receptor Frizzled-9 Regulates New Bone Formation in Fracture Healing |
title_sort | wnt serpentine receptor frizzled-9 regulates new bone formation in fracture healing |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3877253/ https://www.ncbi.nlm.nih.gov/pubmed/24391920 http://dx.doi.org/10.1371/journal.pone.0084232 |
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