D. KASPER & T. JENTSCH
Bone is a dynamic structure, constantly being formed (by cells called osteoblasts) and resorbed (by osteoclasts). The activities of these cells must be finely balanced. If resorption exceeds formation, the result is the weakened, brittle bones characteristic of osteoporosis. In osteopetrosis, by contrast, not enough bone is resorbed: the osteoclasts malfunction, leading to dense yet fragile bones with no bone marrow. Writing in Cell (104, 205–215; 2001), Uwe Kornak, Dagmar Kasper and colleagues identify a molecule that is needed for the bone-resorbing cells to function. Their results may explain some cases of an inherited disease, infantile malignant osteopetrosis.
During bone resorption, osteoclasts attach to the bone matrix and form a specialized outer membrane, called the ruffled border, facing the bone. Bone-digesting enzymes are then transported out of the cell, across this border. The enzymes need an acidic environment to function, so the osteoclasts also pump out protons. At the same time, chloride ions are let out of the cell to maintain the electrical balance. The protein-based channel that selectively allows the efflux of chloride ions has been elusive, but the authors suggest that it is a molecule called ClC-7.
Kornak et al. engineered mice with a disruption in the gene encoding ClC-7.The resulting mutant mice (one of which is pictured above, with a normal mouse) had all the characteristics of osteopetrosis, including short limbs and abnormally dense bones. The mice also failed to form bone marrow, as can be seen by comparing the two high-magnification X-ray images above. Moreover, osteoclasts isolated from the mutant mice were unable to absorb bone.
The authors tracked down the ClC-7 protein to the outer membrane and certain acidic organelles, called lysosomes, in the osteoclasts of normal mice. But there was no ClC-7 protein in these cells in the mutant mice. Although the osteoclasts from the mutant mice contained the usual proton pump in their outer membranes, they were unable to acidify the extracellular space — presumably because of the defect in ClC-7. Finally, Kornak et al. discovered that a patient with infantile malignant osteopetrosis has a disrupted ClC-7 gene. All in all, they make a convincing case that this chloride channel is crucial for bone resorption.
