Bard: Although most of the work of this symposium rightly focuses on the signals that make mesenchyme form condensations and the subsequent regulatory pathways that lead to bone formation and growth, I don't think that we are paying enough attention to the events taking place within the condensation itself.
There are three obvious stages in the formation of endochondral bones: (1) making the initial condensation, (2) establishing the future pattern of the bone, and (3) the subsequent steps of differentiation, morphogenesis and growth. In the case of the forelimb, for example, the initial proximal—distal set of condensations that form only demarcates the basic pattern of a single humerus, a radius—ulnar doublet, a condensation that will form the carpal bones, and the five pre-digit condensations. It should also be pointed out that some of these condensations merge with proximal and distal ones. The next step is the exact delineation of the bones and this seems to take place within each condensation in an autonomous way. Only after this has been done can the subsequent events of differentiation, morphogenesis and growth take place.
The purpose of this brief comment is to take a simple look at the events taking place within the condensation, the least understood part ofbone development. The formation and differentiation of mesenchymal condensations is not, of course, a process limited to the limb; it is the normal mode of development for a wide variety of mesenchyme-based tissues that include muscles, dermal derivatives (e.g. feather and hair papillae), teeth and nephrons, as well as bones. It should however be pointed out that, although condensation formation is a key stage in the differentiation of these tissues, there is not a single case where we understand how bringing cells close together (by loss of matrix, migration, the production of adhesion molecules) changes their co-operative properties and so allows them to set out on a new developmental pathway.
An interesting example is the formation of the nephron: here, signalling from the epithelial duct instructs a small group of metanephric mesenchyme cells to condense (Davies & Bard 1998). Once this has happened, a series of apparently condensation-autonomous events then take place which result in the formation of the nephron. The cells within the condensation undergo a mesenchyme-to-epithelial transition and start to form a tubule that fuses to the duct at one end, and makes a glomerulus at the other, with the tubule as a whole undergoing the extensive differentiation and elongation that marks the nephron. The response is so sophisticated that it is hard to see how the condensation-forming signal can do any more than activate a pathway which is self-controlled and self-sustained and whose molecular underpinnings are only beginning to be understood (Kispert et al 1998).
I wish to suggest that autonomous spatial patterning events of similar complexity take place within the chondrogenic condensation and it is these that specify the map that defines the phenotype of a particular bone. Controlling the downstream cassettes of gene expression that leads to osteogenesis is then as straightforward here as anywhere else; the difficult problem is to work out how patterning takes place within a chondrogenic aggregate.
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