Trends in Molecular Medicine
Osteoclast-derived activity in the coupling of bone formation to resorption
Section snippets
Bone remodelling
The remodelling of bone consists of a strict coupling of bone resorption and formation that continues throughout life and is necessary not only for skeletal growth but also to maintain normal bone structure 1, 2, 3, 4, 5. The process begins with the resorption of a volume of bone by osteoclasts followed by new bone formation by osteoblasts, with a positive balance during growth and a negative balance with ageing. This process takes place in ‘bone multicellular units’ (BMUs) asynchronously
Intercellular communication in bone: osteoclast formation
The importance of local intercellular communication to the regulation of bone-cell function became established after it was proposed that the formation and activity of osteoclasts is controlled by cells of the osteoblast lineage [6]. Osteoclasts, which are the only cells capable of resorbing bone, are multinucleated giant cells formed from hematopoietic precursors of the monocyte and macrophage series. They attach to the bone surface, sealing a resorbing compartment that they acidify by
The coupling factor concept
There is ample evidence that bone formation is coupled to bone resorption. The stimulation of bone resorption in vivo by agents such as PTH and prostaglandin E is accompanied by increased bone formation 3, 4, 12. A local ‘coupling factor’ linking bone resorption to subsequent formation was proposed by Baylink, Howard and colleagues [13] as the key regulator of the remodelling process. The concept developed that coupling might be achieved by the activities of one or more growth factors released
Could the osteoclast produce coupling activity?
Recent studies in genetically manipulated mice provide indications that the osteoclast itself could be the source of an activity that contributes to the fine control that is a feature of the coupling process. The cytokines that signal through gp130 have an important role in intercellular communication processes in bone [9]. By studying mice in which each of the two gp130-dependent signalling pathways were specifically attenuated, inactivation of the SHP2–ras–MAPK signalling pathway (gp130
Evidence from the anabolic action of PTH
Some light might be shed on the connection between the resorption and formation of bone by considering the action of PTH, which has been developed as a highly effective anabolic therapy for the skeleton, despite its best-known action as a resorptive hormone. The anabolic effect requires PTH to be given in an intermittent, rather than a continuous mode [25]. This has been obtained by daily injections, which rapidly achieve a peak level in blood but is not maintained [26]. There are two general
Further evidence from mouse genetics: role of the calcitonin receptor
Evidence of a different nature points further to a role for the activated osteoclast in the coupling process. Mice rendered null for calcitonin (CT−/− mice) have increased bone formation [43], as do those that are deficient in the CT receptor (CTR+/− mice) [44]. These unexpected findings can be explained by the hypothesized role of active osteoclasts. The best-documented action of calcitonin is its acute inhibition of osteoclast function following injection [45]. If the initiation of bone
Implications for disease and therapy
A notable example of the dissociation of coupling bone formation with resorption comes from oestrogen removal following ovariectomy or menopause. Following this, bone remodelling is increased such that more of the bone surface is occupied by BMUs undergoing resorption and formation. Within each BMU, however, the amount of bone resorbed exceeds that which is formed and bone is lost. Attempts have been made to explain the increased resorption and loss of bone with oestrogen withdrawal, such as
Concluding remarks
The important regulatory role of coupling activity is to drive the osteoblast lineage to replace the necessary amount of bone in each BMU. We argue that coupling activity is generated by the activated osteoclast and is required for the full expression of the anabolic action of PTH on bone. This hypothesis could readily be tested by examining the anabolic effect of PTH in appropriate genetically modified mice and in normal mice co-treated with different inhibitors of bone resorption. It is
Acknowledgements
The authors acknowledge the helpful criticism of Ego Seeman and Gideon A. Rodan, and grant support from the NHMRC (Australia).
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