When developmental biology meets human pathology

Many genes, long-known or novel, have been identified as either regulators of cell differentiation or cell function in the skeleton. This identification certainly has improved our understanding of skeleton biology as a whole by providing multiple new pieces to the embryologic and physiologic puzzle (1, 2). However, so far most of these pieces remain unconnected. To date, what has been lacking in skeleton biology is the definition of genetic cascades linking these genes together in a linear fashion to explain complex processes like patterning, cell differentiation, or cell function. A complete explanation also would include the transition steps between the major processes. The work of Motyckova et al. (3) published in this issue of PNAS establishes precisely this type of genetic cascade for the late events of osteoclast cell lineage differentiation.