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Jack Martin, (Melbourne, Australia)

Mechanisms in the coupling of bone resorption and formation

Topics to be covered

Local signalling that results in bone formation during remodelling takes place in several ways. Remodelling begins with bone resorption that is initiated when osteoclast precursors, derived from the circulation and adjacent marrow, most likely through capillary sinusoids in bone remodelling compartments (BRCs), are programmed to differentiate into osteoclasts. These resorb a certain amount of bone and die. The resorption cavity is prepared for the reversal phase, in which the resorbed bone is replaced when incoming osteoblast precursors differentiate and form new bone. Growth factors released from resorbed bone matrix can contribute to preosteoblast differentiation and bone formation. The preosteoblasts themselves, growing in the resorption space, can communicate through cell contact and paracrine signalling mechanisms to differentiate. Osteocytes can sense the need for bone repair by detecting damage and pressure changes, and signalling to surface cells to respond appropriately. Now that it has been shown through mouse genetics that PTHrP generated locally in bone is a crucial physiological regulator of bone formation, and probably also of resorption, we need to understand how local PTHrP release is controlled in bone in the remodelling process, so that it can both promote differentiation of osteoblasts and inhibit their apoptosis.

There is some evidence to support a view that osteoclasts in the BMU might also generate activity that contributes to bone formation, and could even complement the direct effect that PTH has in promoting differentiation of committed osteoblast precursors. First, both human and mouse genetics provide evidence supporting the view that osteoclasts, despite in some circumstances being unable to resorb bone, e.g. failure of acidification or of cathepsin K activity, can nevertheless be associated with normal, or even increased bone formation. An implication is that it may be possible to design resorption inhibitors that do not block bone formation. Second, PTH administered intermittently in an anabolic regime results in transient activation of osteoclasts, and prevention of the latter in a number of experimental approaches has been associated with blunting of the PTH anabolic effect. It is possible that osteoclasts, transiently activated by PTH can contribute to the coupling of bone formation to resorption by producing activity that influences preosteoblast participation in bone formation.

Educational goals

After attending this Meet the Professor session, participants will be expected to:

• understand how osteoblasts and osteoclasts are generated from precursors in bone;
• understand how the cells of bone communicate with each other in the bone remodelling process;
• use this knowledge in thinking about mechanisms and treatment of bone diseases.

Target audience

Basic scientists in bone cell biology, clinicians interested in bone biology and drug action.

Teaching methods

Discussion of topics, question and answer, no slides.