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

Abstract 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.