Figure 4.

Hypothetical model for the transport of late endosomes/lysosomes to the ruffled border in osteoclasts. Rab7 is localized to late endosomes/lysosomes and to the peripheral area of the ruffled border (close to the sealing zone) in osteoclasts and regulates the trafficking of these vesicles toward the plus end of microtubules. The other mediators of this process remain unknown, although the Rab7-binding protein Plekhm1, which is recruited to late endosomes/lysosomes by Rab7, is likely to be involved, since osteoclasts from osteopetrosis patients with mutations in this protein have defective ruffled borders. One possibility is that Plekhm1 may bridge Rab7 and a kinesin motor to enable trafficking to occur on microtubules. Rab7 has been shown to interact directly with Rac1 close to the sealing zone, and it has been postulated that this interaction may mediate the transfer of the late endosomes/lysosomes from the microtubule network to the cortical actin network prior to fusion with the ruffled border acceptor membrane and the release of cathepsin K and acid at the periphery of the RB into the resorption lacuna. This process also serves to insert the V-ATPase, ClC-7 and Rab7 into the ruffled border membrane. The V-ATPase itself may also have a role in this process, since subunits of the pump have been shown to bind to actin microfilaments. Transcytotic vesicles, which are involved in the further degradation and removal of collagen fragments and are trafficked on microtubules to the functional secretory domain (FSD), originate from the central region of the ruffled border; as yet the Rab GTPases governing this pathway remain unknown.