Upstream eventReduced collagen production
Smaller and morphologically distorted facial cartilage structures
Key Event Relationship Overview
AOPs Referencing Relationship
|AOP Name||Adjacency||Weight of Evidence||Quantitative Understanding|
|Histone deacetylase inhibition leads to impeded craniofacial development||adjacent||Not Specified||Not Specified|
Life Stage Applicability
Key Event Relationship Description
The main component of cartilage is collagen, most importantly fibril forming type II collagen which forms the fibrillary scaffold to which other proteoglycans can crosslink (Van Der Rest and Mayne, 1988).
The expression and secretion of collagen from chondrocytes are vitally important to the morphological development and mechanical properties of cartilage structures.
Evidence Supporting this KER
The advent of the bony skeleton marks a significant evolutionary event and as such the evolution of the key components in its development has been studied extensively. The Sox9 regulated collagen secretion in cartilage development has been found to be a highly evolutionarily conserved feature (Zhang et al., 2006). It has been shown in several organisms that loss of function mutations in genes encoding collagens exhibit severe phenotypic manifestations in cartilages and cartilage-derived tissues (Vuorio and de Crombrugghe, 1990). In zebrafish, the reduced expression of otherwise functional type II collagen, due to a mutation in the Sox9 encoding gene, was characterized by severely retarded craniofacial cartilage formation (Yan et al., 2002).
A mouse mutant in type II collagen is severely deficient in cartilage formation (Garofalo et al., 1991).
In zebrafish, antisense knock-down of col11a1, another fibrillar collagen, was found to cause severe attenuation of craniofacial cartilage development (Baas et al., 2009).
Uncertainties and Inconsistencies
While it is quite well established that fibrillar collagens, such as collagen 2a and collagen 11a, are important to normal cartilage formation, and that null and dominant negative mutations will cause certain strong phenotypic manifestations within cartilage structures, it is less well established how reduced collagen expression will affect such structures. Whether measurable morphological manifestations, such as e.g. differing angles, diameters or lengths, of cartilage features, are in fact caused by attenuated cartilage expression or simply correlated with it, is unknown.
Quantitative Understanding of the Linkage
Known modulating factors
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Baas, D., Malbouyres, M., Haftek-Terreau, Z., Guellec, D. Le, and Ruggiero, F. (2009), Matrix Biol 28: 490–502.
Garofalo, S., Vuorio, E., Metsaranta, M., Rosati, R., Toman, D., Vaughan, J., et al. (1991), Proc Natl Acad Sci U S A 88: 9648–9652.
Rest, M. Van Der, and Mayne, R. (1988), J Biol Chem 263: 1615–1618.
Vuorio, E., and Crombrugghe, B. de (1990), Annu Rev Biochem 59: 837–72
Yan, Y.L., Miller, C.T., Nissen, R.M., Singer, A., Liu, D., Kirn, A., et al. (2002), Development 129: 5065–5079
Zhang, G., Miyamoto, M.M., and Cohn, M.J. (2006), Proc Natl Acad Sci U S A 103: 3180–3185.