Regulation of articular chondrocyte proliferation and differentiation by indian hedgehog and parathyroid hormone-related protein in mice.
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.


CONCLUSIONS
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.
Chen
Xuesong
X
Yale University School of Medicine, New Haven, Connecticut 06520-8020, USA.
Macica
Carolyn M
CM
Nasiri
Ali
A
Broadus
Arthur E
AE
D000818:Animals; D002358:Cartilage, Articular / Q000166:cytology* / Q000254:growth & development; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D019902:Chondrocytes / Q000166:cytology* / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental; D055879:Gene Knock-In Techniques; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D006818:Hyalin / Q000378:metabolism; D007763:Lac Operon; D051379:Mice; D008822:Mice, Transgenic; D044162:Parathyroid Hormone-Related Protein / Q000235:genetics* / Q000378:metabolism; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000235:genetics / Q000378:metabolism; D016474:Weight-Bearing / Q000502:physiology
D053823:Hedgehog Proteins; D044162:Parathyroid Hormone-Related Protein; D044168:Receptor, Parathyroid Hormone, Type 1; C514061:ihh protein, mouse