Osteoclasts and bone resorption: cellular and molecular mechanisms

Recent-advances in the understanding of the differentiation and function of osteoclasts, which are responsible for bone resorption, have considerably improved our knowledge of bone remodeling. Thus, the ning of stromal-derived RANK and and its antagonist Osteoprotegerin has been a major breakthrough Tie dissection of the differentiation steps leading from pro-monocytes to maturing osteoclasts in the bone marrow. Precise analysis of the distribution of the actin skeletton, arranged structures called podosomes, has also helped to understand the motile properties of the osteoclasts and how it can alternate adhesion and de-adhension from its bone substrate. The succession of of complex biochemical events involved in bone resorption has also been unraveled: osteoclasts are highly polarized cells, and this asymetry is essential: the apical border facing the bone surface is tightly sealed to the bone on the periphery, whereas degrading enzymes and metalloproteases are secreted through the ruffled border in the central part. Acidification is essential to the function of osteoclasts and-is maintained by several pumps and ions channels, such as a unique ATPase on the apical side as well as chloride channels, and NA(+)/H+ pump on the basal side. Genetic models exists where some of these steps are altered, which lead to bone disorders, either by excess resorption (osteoporosis) or by decreased resorption, as in osteosclerosis. Most of these alterations target molecules (growth factors or transcription factors) controlling the differentiation process.