Transient activation of Wnt/{beta}-catenin signaling induces abnormal growth plate closure and articular cartilage thickening in postnatal mice.
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.
Yuasa
Takahito
T
Department of Orthopedic Surgery, Thomas Jefferson University, Philadelphia, PA 19107, USA.
Kondo
Naoki
N
Yasuhara
Rika
R
Shimono
Kengo
K
Mackem
Susan
S
Pacifici
Maurizio
M
Iwamoto
Masahiro
M
Enomoto-Iwamoto
Motomi
M
D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D001842:Bone and Bones / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D002358:Cartilage, Articular / Q000002:abnormalities* / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology / Q000378:metabolism; D024161:Collagen Type XI / Q000235:genetics / Q000378:metabolism; D006132:Growth Plate / Q000002:abnormalities* / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D007719:Knee Joint / Q000002:abnormalities / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D015398:Signal Transduction / Q000502:physiology*; D013629:Tamoxifen / Q000494:pharmacology; D051153:Wnt Proteins / Q000235:genetics / Q000378:metabolism*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism*
D050071:Bone Density Conservation Agents; D024161:Collagen Type XI; D051153:Wnt Proteins; D051176:beta Catenin; D013629:Tamoxifen