Genetic evidence of the regulatory role of parathyroid hormone-related protein in articular chondrocyte maintenance in an experimental mouse model.

OBJECTIVE

Parathyroid hormone-related protein (PTHrP) regulates the rate of differentiation of growth chondrocytes and is also expressed in articular chondrocytes. This study tested the hypothesis that PTHrP might have a regulatory role in articular chondrocyte maintenance.

METHODS

Control sequences of growth differentiation factor 5 were used to delete PTHrP from articular chondrocytes in the mid-region of mouse articular cartilage. Mice with conditional deletion of PTHrP (knockout [KO]) and littermate control mice were evaluated for degenerative changes using both a time-course design and destabilization of the medial meniscus (DMM) technique. A total histologic score of degenerative changes was determined for the femoral and tibial articular surfaces (total maximum score of 60).

RESULTS

The time-course study revealed degenerative changes in only a minority of the KO mice. In the DMM model, male KO mice were highly susceptible to DMM-induced degenerative changes (mean ± SEM total histologic score 45 ± 2.7 in KO mice versus 23 ± 1.4 in controls; P < 0.0001 by Mann-Whitney U test), with virtually no overlap between groups. PTHrP normally functions in a feedback loop with Indian hedgehog (IHH), in which a reduction in one signaling partner induces a compensatory increase in the other. A number of phenotypic and functional markers were documented in KO mice to suggest that the IHH-PTHrP axis is capable of compensating in response to a partial Cre-driven PTHrP deletion, a finding that underscores the need to subject the mouse articular cartilage to a destabilizing challenge in order to elicit frankly degenerative findings.

CONCLUSION

PTHrP may regulate articular chondrocyte maintenance in mice.