Absence of collagen IX accelerates hypertrophic differentiation in the embryonic mouse spine through a disturbance of the Ihh-PTHrP feedback loop.
Collagen IX (Col IX) is a component of the cartilage extracellular matrix and contributes to its structural integrity. Polymorphisms in the genes encoding the Col IX ɑ2- and ɑ3-chains are associated with early onset of disc degeneration. Col IX-deficient mice already display changes in the spine at the newborn stage and premature disc degeneration starting at 6 months of age. To determine the role of Col IX in early spine development and to identify molecular mechanisms underlying disc degeneration, the embryonic development of the spine was analyzed in Col IX -/- mice. Histological staining was used to show tissue morphology at different time points. Localization of extracellular matrix proteins as well as components of signaling pathways were analyzed by immunohistochemistry. Developing vertebral bodies of Col IX -/- mice were smaller and already appeared more compact at E12.5. At E15.5, vertebral bodies of Col IX -/- mice revealed an increased number of hypertrophic chondrocytes as well as enhanced staining for the terminal differentiation markers alkaline phosphatase and collagen X. This correlates with an imbalance in the Ihh-PTHrP signaling pathway at this time point, reflected by an increase of Ihh and a concomitant decrease of PTHrP expression. An accelerated hypertrophic differentiation caused by a disturbed Ihh-PTHrP signaling pathway may lead to a higher bone mineral density in the vertebral bodies of newborn Col IX -/- mice and, as a result, to the early onset of disc degeneration.
Center for Biochemistry, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, D-50931, Cologne, Germany.
Matthias
M
Kamper
Center for Biochemistry, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, D-50931, Cologne, Germany.|Center for Molecular Medicine Cologne (CMMC), University of Cologne, D-50931, Cologne, Germany.|Cologne Center for Musculoskeletal Biomechanics (CCMB), University of Cologne, D-50931, Cologne, Germany.|Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, D-50931, Cologne, Germany.
Mats
M
Paulsson
Center for Biochemistry, Medical Faculty, University of Cologne, Joseph-Stelzmann-Str. 52, D-50931, Cologne, Germany. frank.zaucke@uni-koeln.de.|Cologne Center for Musculoskeletal Biomechanics (CCMB), University of Cologne, D-50931, Cologne, Germany. frank.zaucke@uni-koeln.de.|Dr. Rolf M. Schwiete Research Unit for Osteoarthritis, Orthopedic University Hospital, Friedrichsheim gGmbH, D-60528, Frankfurt/Main, Germany. frank.zaucke@uni-koeln.de.
Frank
F
Zaucke
D000818:Animals; D002454:Cell Differentiation; D024043:Collagen Type II / Q000378:metabolism; D024081:Collagen Type IX / Q000172:deficiency* / Q000378:metabolism; D004622:Embryo, Mammalian / Q000473:pathology*; D025461:Feedback, Physiological; D053823:Hedgehog Proteins / Q000378:metabolism*; D006984:Hypertrophy; D008159:Lumbar Vertebrae / Q000196:embryology; D051379:Mice; D008810:Mice, Inbred C57BL; D044162:Parathyroid Hormone-Related Protein / Q000378:metabolism*; D013131:Spine / Q000196:embryology* / Q000473:pathology*
D024043:Collagen Type II; D024081:Collagen Type IX; D053823:Hedgehog Proteins; D044162:Parathyroid Hormone-Related Protein; C514061:ihh protein, mouse
Cartilage; Collagen; Extracellular matrix; Intervertebral disc; Spine