Mice lacking link protein develop dwarfism and craniofacial abnormalities
Hideto Watanabe
& Yoshihiko Yamada
Craniofacial Developmental Biology and Regeneration
Branch, National Institute of Dental and Craniofacial Research, National Institutes
of Health, Bethesda, Maryland 20892,
USA.
Link protein (LP), an extracellular matrix protein in cartilage, stabilizes
aggregates of aggrecan and hyaluronan, giving cartilage its tensile strength
and elasticity1,
2,
3. Cartilage provides the template for endochondral
ossification and is crucial for determining the length and width of the skeleton.
During endochondral bone formation, hypertrophic chondrocytes die and the
cartilage is replaced with bone matrix. Here, we have generated targeted mutations
in mice in the gene encoding LP (Crtl1). Homozygotes showed defects
in cartilage development and delayed bone formation with short limbs and craniofacial
anomalies. Most Crtl1tm1Nid/tm1Nid mice died shortly
after birth due to respiratory failure, but some survived and developed progressive
dwarfism and lordosis of the cervical spine. They showed small epiphysis,
slightly flared metaphysis of long bones and flattened vertebrae, characteristic
of spondyloepiphyseal dysplasias. The cartilage contained significantly reduced
aggrecan depositions in the hypertrophic zone, and decreased numbers of prehypertrophic
and hypertrophic chondrocytes. Reduced Indian hedgehog (Ihh) expression was
observed in prehypertrophic chondrocytes, and apoptosis was inhibited in hypertrophic
chondrocytes. These results indicate that LP is important for the formation
of proteoglycan aggregates and normal organization of hypertrophic chondrocytes,
and suggest that cartilage matrix has a role in chondrocyte differentiation
and maturation.
