Osteoclasts are multinucleated cells responsible for bone resorption. During the resorption cycle, osteoclasts undergo dramatic changes in their polarity, and resorbing cells reveal four functionally and structurally different membrane domains. Bone degradation products, both organic and inorganic, were endocytosed from the ruffled border membrane. They were then found to be transported in vesicles through the cell to the plasma membrane domain, located in the middle of the basal membrane, where they were liberated into the extracellular space. These results explain how resorbing osteoclasts can simultaneously remove large amounts of matrix degradation products and penetrate into bone.

Subosteoclastic bone resorption is a result of HCl and proteinase secretion through a late endosome-like bone facing membrane domain called ruffled border. As bone matrix is degraded, it enters osteoclasts' transcytotic vesicles for further processing and is then finally exocytosed to the intercellular space. The present study clarifies the spatial relationship between these vesicle fusion and matrix uptake processes at the ruffled border. Our results show the presence of vacuolar H π -ATPase, small GTPase rab7 as well as dense aggregates of F-actin at the peripheral ruffled border, where basolaterally endocytosed transferrin and cathepsin K are delivered. On the contrary, rhodamine-labeled bone matrix enters transcytotic vesicles at the central ruffled border, where the vesicle budding proteins such as clathrin, AP-2 and dynamin II are also localized. We present a model for the mechanism of ruffled border turnover and suggest that, due to its late endosomal characteristics, the ruffled border serves as a valuable model for studying the dynamic organization of other endosomal compartments as well.

No abstract

There is ample evidence now that the two major events in bone resorption, namely dissolution of hydroxyapatite and degradation of the organic matrix, are performed by osteoclasts. The resorption cycle involves several specific cellular activities, where intracellular vesicular trafficking plays a crucial role. Although details of these processes started to open up only recently, it is clear that vesicular trafficking is needed in several specific steps of osteoclast functioning. Several plasma membrane domains are formed during the polarization of the resorbing cells. Multinucleated osteoclasts create a tight sealing to the extracellular matrix as a first indicator of their resorption activity. Initial steps of the sealing zone formation are alpha(v)beta(3)-integrin mediated, but the final molecular interaction(s) between the plasma membrane and mineralized bone matrix is still unknown. A large number of acidic intracellular vesicles then fuse with the bone-facing plasma membrane to form a ruffled border membrane, which is the actual resorbing organelle. The formation of a ruffled border is regulated by a small GTP-binding protein, rab7, which indicates the late endosomal character of the ruffled border membrane. Details of specific membrane transport processes in the osteoclasts, e.g., the formation of the sealing zone and transcytosis of bone degradation products from the resorption lacuna to the functional secretory domain remain to be clarified. It is tempting to speculate that specific features of vesicular trafficking may offer several potential new targets for drug therapy of bone diseases.