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The Journal of Bone and Joint Surgery (American) 85:124-132 (2003)
© 2003 The Journal of Bone and Joint Surgery, Inc.

Scientific Article

Molecular Mechanisms Regulating Chondroblast Differentiation

Lisa M. Hoffman, PhD*, Andrea D. Weston, PhD* and T. Michael Underhill, PhD

*Lisa M. Hoffman, PhD, and Andrea D. Weston, PhD, contributed equally to the preparation of this article.

Corresponding author: T. Michael Underhill, PhD
Department of Physiology, Faculty of Medicine and Dentistry, The University of Western Ontario, London, Ontario, Canada N6A 5C1. E-mail address: tunderhi{at}uwo.ca

In support of their research or preparation of this manuscript, one or more of the authors received grants or outside funding from Canadian Institutes of Health Research, the Canadian Arthritis Network, and the National Sciences and Engineering Research Council of Canada. None of the authors received payments or other benefits or a commitment or agreement to provide such benefits from a commercial entity. No commercial entity paid or directed, or agreed to pay or direct, any benefits to any research fund, foundation, educational institution, or other charitable or nonprofit organization with which the authors are affiliated or associated.

Background: Formation of the cartilage template involves a multi-step process in which prechondrogenic mesenchymal cells form condensations prior to differentiating into matrix-producing chondroblasts. Retinoids, particularly retinoic 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 skeletogenesis. 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-{alpha}) in their developing limbs were generated. The mice presented with a range of skeletal abnormalities. To examine the mechanisms responsible for these abnormalities, 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 evaluation 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.

Results: The evidence reviewed here indicates that retinoids maintain cells within condensations in a prechondrogenic, mesenchymal cell state, which prevents the cells from differentiating into chondroblasts. More recent studies have demonstrated that the inhibition of receptor-mediated retinoid signaling induces the expression of Sox9, a transcription factor that is considered a "master switch" for the differentiation of chondroblasts. These effects are largely mediated by the activation of the p38 MAPK signaling cascade.

Conclusions: These findings demonstrate that retinoid receptor-mediated repression is both necessary and sufficient for chondroblast differentiation. Moreover, retinoic acid receptor repression acts downstream of BMP signaling or in a distinct pathway to activate p38 MAPK, which in turn induces chondroblast differentiation.


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