Transient Activation of Wnt/{beta}-Catenin Signaling Induces Abnormal Growth Plate Closure and Articular Cartilage Thickening in Postnatal Mice

• Published in: The American journal of pathology Vol. 175; no. 5; p. 1993
• Main Authors: Yuasa, Takahito, Kondo, Naoki, Yasuhara, Rika, Shimono, Kengo, Mackem, Susan, Pacifici, Maurizio, Iwamoto, Masahiro, Enomoto-Iwamoto, Motomi
• Format: Journal Article
• Language: English
• Published: United States ASIP 01.11.2009
• Subjects: Animals; beta Catenin - genetics; beta Catenin - metabolism; Bone and Bones - anatomy & histology; Bone and Bones - drug effects; Bone and Bones - metabolism; Bone and Bones - pathology; Bone Density Conservation Agents - pharmacology; Cartilage, Articular - abnormalities; Cartilage, Articular - drug effects; Cartilage, Articular - metabolism; Cartilage, Articular - pathology; Cells, Cultured; Chondrocytes - cytology; Chondrocytes - metabolism; Collagen Type XI - genetics; Collagen Type XI - metabolism; Growth Plate - abnormalities; Growth Plate - drug effects; Growth Plate - metabolism; Growth Plate - pathology; Humans; Knee Joint - abnormalities; Knee Joint - pathology; Knee Joint - physiopathology; Mice; Mice, Inbred C57BL; Mice, Transgenic; Signal Transduction - physiology; Tamoxifen - pharmacology; Wnt Proteins - genetics; Wnt Proteins - metabolism
• ISSN: 0002-9440; 1525-2191
• DOI: 10.2353/ajpath.2009.081173

Wnt/beta-catenin signaling is required for skeletal development and organization and for function of the growth plate and articular cartilage. To further clarify these roles and their possible pathophysiological importance, we created a new transgenic mouse model in which Wnt/beta-catenin signaling can be activated in cartilage for specific periods of time. These transgenic mice expressed a constitutive active form of beta-catenin fused to a modified estrogen receptor ligand-binding domain under the control of cartilage-specific collagen 11alpha2 promoter/enhancer. Transient Wnt/beta-catenin signaling activation in young adult mice by tamoxifen injections induced growth retardation and severe deformities in knee joints. Tibial and femoral growth plates displayed an excessive number of apoptotic cells and eventually underwent abnormal regression. Articular cartilage exhibited an initial acute loss of proteoglycan matrix that was followed by increases in thickness, cell density, and cell proliferation. In reciprocal studies, we found that conditional ablation of beta-catenin in postnatal mice using a Col2-CreER strategy led to hypocellularity in articular cartilage, growth plate disorganization, and a severe reduction in bone volume. Together, these data provide evidence that Wnt/beta-catenin signaling has important and distinct roles in growth plate and articular cartilage and that postnatal dysregulation of this signaling pathway causes diverse structural and functional changes in the two cartilaginous structures.