Conditional Deletion of PTHrP in Articular Chondrocytes

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We have created a PTHrP-lacZ knock-in mouse, which serves as a sensitive PTHrP gene expression system. Findings in this mouse suggest that existing interpretations as to PTHrP functions in endochondral bone may need to be refined. The chondroepiphysis (CE) is the primordial epiphyseal growth zone in lower forms such as teleosts and is also the structure that drives linear growth during embryogenesis in terrestrial mammals. The proliferative chondrocytes of the CE express PTHrP, and it is this stage of prenatal development that has been focused upon almost exclusively in the published work. At postnatal day 7-10 in the mouse, the secondary ossification center forms and subdivides the PTHrP-expressing chondrocytes into two subpopulations, one associated with the growth plate and a second that will become articular chondrocytes (AC). The PTH-1 receptor-expressing prehypertrophic chondrocytes lie immediately subjacent to the PTHrP-expressing ACs, in a fashion that excludes mineralizing hypertrophic chondrocytes from the ACs and joint space. PTHrP expression in ACs is load-depend, and unloading a joint in vivo leads to a suppression in PTHrP/(3 gal expression and a large increase in hypertrophic chondrocytes that approach the articular surface. We propose here to conditionally delete PTHrP in ACs using a Gdf5-Cre mouse. This system will allow a detailed study of the working hypothesis that PTHrP normally functions to regulate the chondrocyte differentiation program in ACs, as it does elsewhere. The system may also provide a valuable mouse model of osteoarthritis.