COPYRIGHT © 2003 BY THE JOURNAL OF BONE AND JOINT SURGERY, INCORPORATED Molecular Mechanisms Regulating Chondroblast

Background: Formation of the cartilage template involves a multi-step process in which prechondrogenic mesenchy-mal cells form condensations prior to differentiating into matrix-producing chondroblasts. Retinoids, particularly reti-noic acid, are among the numerous signaling molecules that have been implicated in this process. A proper balance of retinoids is essential for normal skeletal development in that too much or too little negatively impacts skeletogen-esis. During the past few years, substantial advances have been made in our understanding of the role of retinoid signaling in these processes, which is reviewed in this report. Methods: To examine the function of retinoid signaling in skeletal development, transgenic mice that overexpressed a weak, constitutively active retinoic acid receptor (retinoic acid receptor-α) in their developing limbs were generated. The mice presented with a range of skeletal abnormalities. To examine the mechanisms responsible for these abnor-malities, primary limb mesenchymal cultures from the transgenic mice were compared with cultures from wild-type mice. In addition, to address the molecular basis of retinoic acid receptor action, retinoic acid receptor activity in the primary cultures was manipulated with use of retinoic acid receptor-selective agonists and antagonists. The evalua-tion of the response to the manipulation of retinoic acid receptors was followed by histological studies and by the use of Northern blot analysis and reporter assays to analyze changes in the expression of chondrocytic markers and to monitor transcription factor activity, respectively