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© The Rockefeller University Press, 0021-9525/1998//1399 $5.00
The Journal of Cell Biology, Volume 143, Number 5, , 1998 1399-1412

Article

Collagen II Is Essential for the Removal of the Notochord and the Formation of Intervertebral Discs



Attila Aszódi*,{ddagger}, Danny Chan§, Ernst Hunziker||, John F. Bateman§, and Reinhard Fässler*,{ddagger}

* Department of Experimental Pathology, Lund University, 22185 Lund, Sweden; {ddagger} Max Planck Institute for Biochemistry, 82152 Martinsried, Germany; § Department of Paediatrics, University of Melbourne, Victoria 3052, Australia; and || M.E. Müller-Institute for Biomechanics, University of Bern, 3010 Bern, Switzerland

Collagen II is a fibril-forming collagen that is mainly expressed in cartilage. Collagen II–deficient mice produce structurally abnormal cartilage that lacks growth plates in long bones, and as a result these mice develop a skeleton without endochondral bone formation. Here, we report that Col2a1-null mice are unable to dismantle the notochord. This defect is associated with the inability to develop intervertebral discs (IVDs). During normal embryogenesis, the nucleus pulposus of future IVDs forms from regional expansion of the notochord, which is simultaneously dismantled in the region of the developing vertebral bodies. However, in Col2a1-null mice, the notochord is not removed in the vertebral bodies and persists as a rod-like structure until birth. It has been suggested that this regional notochordal degeneration results from changes in cell death and proliferation. Our experiments with wild-type mice showed that differential proliferation and apoptosis play no role in notochordal reorganization. An alternative hypothesis is that the cartilage matrix exerts mechanical forces that induce notochord removal. Several of our findings support this hypothesis. Immunohistological analyses, in situ hybridization, and biochemical analyses demonstrate that collagens I and III are ectopically expressed in Col2a1-null cartilage. Assembly of the abnormal collagens into a mature insoluble matrix is retarded and collagen fibrils are sparse, disorganized, and irregular. We propose that this disorganized abnormal cartilage collagen matrix is structurally weakened and is unable to constrain proteoglycan-induced osmotic swelling pressure. The accumulation of fluid leads to tissue enlargement and a reduction in the internal swelling pressure. These changes may be responsible for the abnormal notochord removal in Col2a1-null mice.

Our studies also show that chondrocytes do not need a collagen II environment to express cartilage-specific matrix components and to hypertrophy. Furthermore, biochemical analysis of collagen XI in mutant cartilage showed that {alpha}1(XI) and {alpha}2 (XI) chains form unstable collagen XI molecules, demonstrating that the {alpha}3(XI) chain, which is an alternative, posttranslationally modified form of the Col2a1 gene, is essential for assembly and stability of triple helical collagen XI.

Key Words: collagen II • notochord • vertebral column • intervertebral disc • development

Abbreviations used in this paper: BrdU, bromodeoxyuridine; CMP, cartilage matrix protein; COMP, cartilage oligomeric protein; IVD, intervertebral disc; TUNEL, terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling.

Address all correspondence to Reinhard Fässler, Department of Experimental Pathology, Lund University, S-22185 Lund, Sweden. Tel.: 46 46 173400. Fax: 46 46 158202. E-mail: reinhard.fassler{at}pat.lu.se


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