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Relationship: 1804


A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

Reduced collagen production leads to Smaller and morphologically distorted facial cartilage structures

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Histone deacetylase inhibition leads to impeded craniofacial development adjacent Not Specified Not Specified Agnes Aggy (send email) Under Development: Contributions and Comments Welcome

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help

Sex Applicability

An indication of the the relevant sex for this KER. More help

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

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 Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

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).

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

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.

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help


List of the literature that was cited for this KER description. More help

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.