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J. Cell Biol.,
Volume 143, Number 5, November 30, 1998 1399-1412
* Department of Experimental Pathology, Lund University, 22185 Lund, Sweden; 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 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
1(XI) and 2 (XI) chains form unstable
collagen XI molecules, demonstrating that the 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.
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