No substitute for β3 integrin

Thanks to some big-boned mice, Zou and Teitelbaum determined how osteoclasts get along without a key signaling protein.

Osteoclasts continually break down bone as part of the skeleton’s normal repair and regeneration. When an osteoclast attaches to bone, the cell’s cytoskeleton rearranges to form a tight seal. A signaling complex that contains αvβ3 integrin detects bone and triggers this cytoskeletal reorganization. Another component of the complex is Dap12. The bones of mice lacking the αvβ3 integrin are only slightly more dense than normal, as are the bones of mice lacking Dap12. The skeletal effects of Dap12 loss might be minimal because another protein, FcRγ, can substitute for it.

Zou and Teibelbaum examined the bones of mice lacking Dap12 and β3 integrin. They expected that the animals would have marginally thicker bones than mice deficient in only one of the proteins. Instead, the double knockout mice had massive, dense bones. Their osteoclasts were puny, attached weakly to bone, and showed a distorted cytoskeleton.

In contrast, the bones of mice missing β1 integrin and Dap12 were no different from the bones of mice lacking Dap12 alone. That result suggested that FcRγ requires β3 to replace Dap12. The researchers tested this idea by determining whether the signaling complex transmits a “dissolve bone” message, a sign that it has been activated. FcRγ and its co-receptor OSCAR send this signal in osteoclasts lacking Dap12 but not in cells missing Dap12 and β3.

The osteoclast signaling complex therefore comes in two forms. One version usually includes Dap12 and αvβ3 integrin, but β1 can stand in for β3. The other combination includes FcRγ instead of Dap12 and can’t function unless it contains β3.