SEMINAR: CMCA Seminar Series: Journey to the Centre of the Osteoclast
|CMCA Seminar Series: Journey to the Centre of the Osteoclast : Current insights and perspectives into the molecular mechanisms of bone resorption.
Osteoclasts are large multinucleated cells formed by the fusion of mononuclear precursors of the monocyte-macrophage lineage whose exclusive function is the degradation of bone. Excessive osteoclast numbers and/or activity underlie a number of debilitating orthopaedic-related diseases including osteoporosis, osteoarthritis and tumour-mediated bone loss, among which osteoporosis is endemic in western society.
To achieve their specialised resorptive function, these polykaryons are endowed with a unique set of molecular machinery following their structural and functional maturation. Upon attachment to bone, the osteoclastic cytoskeleton undergoes dramatic reorganisation culminating in the formation of the F-actin ring/sealing zone which serves to isolate the underlying resorptive compartment from the extracellular space. Concomitant with this event, the osteoclast surface segregates into four interconnected but functionally distinct membrane domains of which the ruffled border is most distinguished and acts as the resorptive organelle.
The ruffled border is formed by the targeted fusion of intracellular acidified vesicles with the bone-apposed plasmalemma. This results in the vectorial release of protons and lysosomal enzymes, such as cathepsin K, into the resorptive space to dissolve bone mineral and organic matrix, respectively. To maintain the continuous flux of membrane at the ruffled border during bone resorption, osteoclasts have evolved robust and flexible vesicular trafficking routes along with specialised transport machinery.
Despite major advances in our understanding of osteoclast biology in the past few decades, the identities and nature of the regulatory mechanisms governing ruffled border formation and function remains largely obscure. We and others have recently unveiled several core components of the osteoclastic resorptive machinery including accessory subunits of the V-ATPase complex, vesicle-associated Rab GTPases and candidate Rab-effector molecules, all which play distinct yet overlapping roles during osteoclastic bone resorption. These and other molecules that contribute to the resorptive function of osteoclasts will be discussed along with their therapeutic potential as anti-resorptive targets.
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