ONSIDERATION OF RECENT REPORTS on the involvement C of the c-src protooncogene in the expression of the osteopetrotic phenotype, in light of the fact that actin-associated proteins are substrata for the src tyrosine kinase, together with new ultrastructural descriptions of the osteoclast/bone interface, has led me to reexamine the role of podosomes in osteoclast adhesion and bone resorption. Here 1 briefly review podosome morphology and dynamics and then speculate on some aspects of podosome biology that I believe need further analysis. An active osteoclast in vivo is characterized by its ruffled border and the annular zone surrounding it, known as the “clear zone” on the basis of its paucity of cellular organelles. The clear zone is also known as the “sealing zone” because the plasma membrane in this region comes into intimate apposition with the bone surface, apparently sealing off a compartment underneath the osteoclast and ruffled border that is compositionally different from the rest of the undersurface and within which bone is resorbed (for discussion, see Ref. 1). Although termed the clear zone, this region of the osteoclast has been known for many years to be rich in contractile proteins, although structural details were lacking.(z-6) This is of interest because microfilaments (MF; F-actin-containing filaments) are known to play a major role in the structural and functional activity of the cell cortex, in the cytoplasmic protrusion, contraction, and retraction needed for cell movement, and in the adhesive structures known as adhesion plaques, focal contacts, and focal adhesions (reviewed in Refs. 7 and 8). Analyzed in more detail recently by immunofluorescence approaches, the distribution of MF in cultured osteoclasts on glass substrata was found to be similar to that in other highly motile cells, that is, monocytes and macrophages. Thus, in osteoclasts on glass a fine network of MF extends throughout the cytoplasm and a bright ring of MF-containing structures can be seen in the peripheral organellefree zone of cytopla~ m.(~‘’~) The bright ring can be resolved into many distinct F-actin-containing dots. Each F-actin-containing dot is encircled by a “rosette” containing vinculin, a-actinin, and talin,(l3-I5) all proteins known to be involved in the regulation of actin polymerization (’6) and the ability of MF to associate with the membrane in adhesive structures, such as focal contacts and focal adhesions.(’) Focal contacts and focal adhesions are the best studied of transmembrane adhesion complexes, in which MF located in the cytoplasm are linked via transmembrane receptors of the integrin family to extracellular, arginineglycine-aspartic acid (RGD)-containing proteins including fibronectin and vitronectin (for reviews, see Refs. 17-19). However, interference reflection microscopy (IRM) of osteoclasts well spread on a glass substratum showed that osteoclasts lack focal contacts and focal adhesions but the bright ring of F-actin-containing structures at the cell periphery corresponds to a broad band of grey reflection or area of close contact (-30 nm between the plasma membrane and substratum). Each individual F-actin dot and rosette structure appears to correspond to one round grey reflection or close contact.(‘2 13) In osteoclasts, these complex F-actin-containing close contact adhesion structures have been termed podosomes by analogy with the same or similar structures in other cell^.('^.'^) The kinds of membrane receptors involved in close contact formation are only beginning to be studied. In this regard, a &-containing integrin, possibly the vitronectin receptor, colocalizes with talin and vinculin in the podosomes of osteoclasts on glass (15)(see also …