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Rev Endocr Metab Disord (2006) 7:123139 DOI 10.1007/s11154-006-9009-x
Molecular regulation of osteoclast activity
Angela Bruzzaniti & Roland Baron
Published online: 2 September 2006 # Springer Science + Business Media, LLC 2006
Abstract Osteoclasts are multinucleated cells derived from hematopoietic precursors that are primarily responsible for the degradation of mineralized bone during bone development, homeostasis and repair. In various skeletal disorders such as osteoporosis, hypercalcemia of malignancy, tumor metastases and Pagets disease, bone resorption by osteoclasts exceeds bone formation by osteoblasts leading to decreased bone mass, skeletal fragility and bone fracture. The overall rate of osteoclastic bone resorption is regulated either at the level of differentiation of osteoclasts from their monocytic/macrophage precursor pool or through the regulation of key functional proteins whose specific activities in the mature osteoclast control its attachment, migration and resorption. Thus, reducing osteoclast numbers and/or decreasing the bone resorbing activity of osteoclasts are two common therapeutic approaches for the treatment of hyper-resorptive skeletal diseases. In this review, several of the key functional players involved in the regulation of osteoclast activity will be discussed.
Keywords Osteoclast . Resorption . Podosome . Signaling . Integrins . Src . Cytoskeleton
1 Functional features of the osteoclast
Several main morphological and functional features define the activity of an osteoclast. These include adherence to the
bone surface, the ability to migrate efficiently toward and along bone surfaces, synthesis and directional secretion of hydrolytic enzymes, acidification of the subosteoclastic bone resorbing compartment by vacuolar proton pumps (V-ATPase) and efficient internalization of extracellular bone matrix degradation products. As discussed in the following sections, the importance of these functional activities is demonstrated by the fact that genetic ablation of the signaling pathways regulating these processes leads to altered bone resorption and osteopetrosis.
During resorption, osteoclasts undergo cytoskeletal reorganization and cellular polarization resulting in the establishment of a distinct apical membrane (toward the bone surface) and a basolateral membrane domain (away for the bone surface) [13]. The domain facing the bone surface, termed the ruffled border, is the main resorptive organelle of the osteoclast (Fig. 1). This pole of the osteoclast lies against the bone matrix and is equivalent to the apical pole of secretory and/or absorptive epithelial cells such as gastric or intestinal lining cells and is therefore termed the...