Building and maintaining joints by exquisite local control of cell fate

Joanna Smeeton, Amjad Askary, J. Gage Crump

We owe the flexibility of our bodies to sophisticated articulations between bones. Establishment of these joints requires the integration of multiple tissue types: permanent cartilage that cushions the articulating bones, synovial membranes that enclose a lubricating fluid-filled cavity, and a fibrous capsule and ligaments that provide structural support. Positioning the prospective joint region involves establishment of an "interzone" region of joint progenitor cells within a nascent cartilage condensation, which is achieved through the interplay of activators and inhibitors of multiple developmental signaling pathways. Within the interzone, tight regulation of BMP and TGFβ signaling prevents the hypertrophic maturation of joint chondrocytes, in part through downstream transcriptional repressors and epigenetic modulators. Synovial cells then acquire further specializations through expression of genes that promote lubrication, as well as the formation of complex structures such as cavities and entheses. Whereas genetic investigations in mice and humans have uncovered a number of regulators of joint development and homeostasis, recent work in zebrafish offers a complementary reductionist approach toward understanding joint positioning and the regulation of chondrocyte fate at joints. The complexity of building and maintaining joints may help explain why there are still few treatments for osteoarthritis, one of the most common diseases in the human population. A major challenge will be to understand how developmental abnormalities in joint structure, as well as postnatal roles for developmental genes in joint homeostasis, contribute to birth defects and degenerative diseases of joints. For further resources related to this article, please visit the WIREs website.