OBJECTIVE: Chondrocytes of the epiphyseal growth zone are regulated by the 
Indian hedgehog (IHH)-parathyroid hormone-related protein (PTHrP) axis. In 
weight-bearing joints, this growth zone comes to be subdivided by the secondary 
ossification center into distinct articular and growth cartilage structures. The 
purpose of this study was to explore the cells of origin, localization, 
regulation of expression, and putative functions of IHH and PTHrP in articular 
cartilage in the mouse.
METHODS: We assessed IHH and PTHrP expression in an allelic PTHrP-LacZ-knockin 
mouse and several versions of PTHrP-null mice. Selected joints were unloaded 
surgically to examine load-induction of PTHrP and IHH.
RESULTS: The embryonic growth zone appears to serve as the source of 
PTHrP-expressing proliferative chondrocytes that populate both the forming 
articular cartilage and growth plate structures. In articular cartilage, these 
cells take the form of articular chondrocytes in the midzone. In PTHrP-knockout 
mice, mineralizing chondrocytes encroach upon developing articular cartilage but 
appear to be prevented from mineralizing the joint space by IHH-driven surface 
chondrocyte proliferation. In growing and adult mice, PTHrP expression in 
articular chondrocytes is load-induced, and unloading is associated with rapid 
changes in PTHrP expression and articular chondrocyte differentiation.
CONCLUSION: We conclude that the IHH-PTHrP axis participates in the maintenance 
of articular cartilage. Dysregulation of this system might contribute to the 
pathogenesis of arthritis.