The role of PPARgamma in cartilage growth and development using cartilage-specific PPARgamma knockout mice
Cartilage, a connective tissue composed of chondrocytes, provides an intermediate template on which bones are formed. Long bones develop through endochondral ossification, involving coordination between chondrocyte proliferation, differentiation and apoptosis, resulting in bone replacing cartilage. Disturbances in this balance results in skeletal abnormalities, and age-related defects including osteoarthritis (OA). The exact mechanisms that control chondrocyte function and behaviour during growth and development are unknown. Peroxisome proliferator-activated receptor (PPAR) gamma, a transcription factor involved in lipid homeostasis, has recently been suggested to be involved in bone homeostasis. However, PPARγ’s role in cartilage growth and development in vivo is unknown. Therefore, for the first time, this study examines PPARγ’s specific in vivo role in cartilage growth and development using cartilage-specific PPARγ knockout (KO) mice. Conditional KO mice were generated using LoxP/Cre system. Histomorphometric analyses of embryonic and adult mutant mice demonstrate reduced long bone growth, calcium deposition, bone density, vascularity, and delayed primary and secondary ossification. Mutant growth plates are disorganized with abnormal chondrocyte shape, proliferation and differentiation, reduced cellularity, loss of columnar organization, and shorter hypertrophic zones. Isolated mutant chondrocytes and cartilage explants show decreased vascular endothelial growth factor (VEGF)-A and extracellular matrix (ECM) production product expression, and increased matrix metalloproteinase (MMP)-13 expression. Aged mutant mice exhibit accelerated OA-like phenotypes, and enhanced cartilage degradation, synovial inflammation, MMP-13 and MMP-generated neoepitope expression. Our data demonstrate that PPARγ is required for normal skeletal development and homeostasis, and is a critical regulator of cartilage health and physiology in early growth and development and aging.
PPARgamma Osteoarthritis Knockout mice Cartilage growth and development Aging Chondrogenesis Endochondral ossification