It was 1994, and Scott Simonet of Amgen's molecular genetics department in Thousand Oaks, Calif., was looking at some strange X-rays. He had engineered five transgenic mouse lines to overexpress a mysterious secreted protein. The mice looked and behaved normally, but that ordinariness was only skin-deep. "On the X-rays, it was pretty obvious that the long bones had higher bone mineral density," says Simonet. The pelvic and vertebral bones also appeared thicker than usual. It was clear that the mysterious protein played a role in building bone.
Simonet had picked the protein because its DNA sequence partially matched that of a family of cytokine receptors involved in cell death, known as tumor necrosis factor (TNF) receptors. But unlike other TNF receptors, this protein lacked a transmembrane-spanning sequence; instead, it showed features of being secreted. As a protein that is released and flows throughout the body, Simonet suspected it might serve ...
