Endocrine Abstracts

The osteoclast is the cell that resorbs bone. Excessive activity by this cell is responsible for the bone loss that causes osteoporosis. Resorptive activity also appears to provide a ‘soil’ suitable for tumour metastasis to bone. Osteoclasts derive from precursors shared with the mononuclear phagocyte system, which differentiate into osteoclasts under the direction of M-CSF and RANKL. In vitro at least, TFG-beta is an essential cofactor for this process, and it is likely that there are other, poorly-understood environmental cues essential for osteoclastic differentiation, which might act through Immunoreceptor Tyrosine-based Activation Motifs (ITAMs).

Once differentiated, the cells are induced to their resorptive function by contact with bone. The mechanism underlying bone recognition is unknown. Resorption involves the development by the osteoclast of a peripheral ‘sealing zone’, between osteoclast and the bone surface, into which the osteoclast secretes protons (which dissolve bone mineral) and cathepsin K (which dissolves the organic matrix).

It has long been known that bone undergoes continuous resorption and formation throughout life. The processes are coupled in such a way that if bone resorption is inhibited, then bone formation is also suppressed. The mechanism accounting for this dependence of bone formation on resorption is unknown, but it creates a major therapeutic impasse in the treatment of osteoporosis, since if bone loss is prevented, then so is bone formation, so that bone once lost cannot be regained. The mechanism through which this coupling occurs is unknown. It might be that osteoclasts secrete ‘coupling factors’, or release these from bone matrix during resorption, or local bone formation might be a mechanically-induced consequence of weakening of bone caused by resorption. Surprisingly, inhibition of bone resorption by cathepsin K inhibitors has been found not to suppress bone formation. We have evidence that this might be due to the preservation, by inhibition of cathepsin K, of osteoblastic growth factors that are known to be released from bone matrix by demineralisation.