title: 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.
  
  
  CONCLUSIONS
  PTHrP may regulate articular chondrocyte maintenance in mice.
authors.affiliation: Yale University School of Medicine, New Haven, Connecticut, USA.
authors.forename: Carolyn
authors.initials: C
authors.lastname: Macica
authors.forename: Guoying
authors.initials: G
authors.lastname: Liang
authors.forename: Ali
authors.initials: A
authors.lastname: Nasiri
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Broadus
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002358:Cartilage, Articular / Q000378:metabolism* / Q000473:pathology; D019902:Chondrocytes / Q000378:metabolism* / Q000473:pathology; D018450:Disease Progression; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics* / Q000378:metabolism
chemical_list: D044162:Parathyroid Hormone-Related Protein