Osteoclasts: what do they do and how do they do it?
As Americans live longer, degenerative skeletal diseases, such as osteoporosis, become increasingly prevalent. Regardless of cause, osteoporosis reflects a relative enhancement of osteoclast activity. Thus, this unique bone resorptive cell is a prominent therapeutic target. A number of key observations provide insights into the mechanisms by which precursors commit to the osteoclast phenotype and how the mature cell degrades bone. The osteoclast is a member of the monocyte/macrophage family that differentiates under the aegis of two critical cytokines, namely RANK ligand and M-CSF. Tumor necrosis factor (TNF)-alpha also promotes osteoclastogenesis, particularly in states of inflammatory osteolysis such as that attending rheumatoid arthritis. Once differentiated, the osteoclast forms an intimate relationship with the bone surface via the alphavbeta3 integrin, which transmits matrix-derived, cytoskeleton-organizing, signals. These integrin-transmitted signals include activation of the associated proteins, c-src, syk, Vav3, and Rho GTPases. The organized cytoskeleton generates an isolated microenvironment between the cell's plasma membrane and the bone surface in which matrix mineral is mobilized by the acidic milieu and organic matrix is degraded by the lysosomal protease, cathepsin K. This review focuses on these and other molecules that mediate osteoclast differentiation or function and thus serve as candidate anti-osteoporosis therapeutic targets.
Teitelbaum
Steven L
SL
Department of Pathology and Immunology, Washington University School of Medicine, Campus Box 8118, 660 South Euclid Ave., St. Louis, MO 63110, USA. teitelbs@wustl.edu
D000375:Aging / Q000378:metabolism* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D002454:Cell Differentiation; D003599:Cytoskeleton / Q000378:metabolism / Q000473:pathology; D005109:Extracellular Matrix / Q000378:metabolism; D006801:Humans; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D016173:Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D010010:Osteoclasts / Q000378:metabolism* / Q000473:pathology; D010014:Osteolysis / Q000378:metabolism* / Q000473:pathology / Q000628:therapy; D010024:Osteoporosis / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D010447:Peptide Hydrolases / Q000378:metabolism; D011494:Protein Kinases / Q000378:metabolism; D053245:RANK Ligand / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D015398:Signal Transduction; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*
D053245:RANK Ligand; D018124:Receptors, Tumor Necrosis Factor; D014409:Tumor Necrosis Factor-alpha; D016173:Macrophage Colony-Stimulating Factor; D011494:Protein Kinases; D010447:Peptide Hydrolases