Heron, John Kyle; (1999) Mechanisms of bacterially induced bone destruction. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Bacteria implicated in bone diseases contain or produce molecules with potent effects on bone cells. These molecules and their actions on the cells and mediators orchestrating the homeostasis of bone have been the focus of the work presented here. In the first study saline extraction of S. aureus yielded a proteinaceous stimulator of in vitro osteolysis and osteoclastogenesis. This osteoclastogenesis could be blocked with calcitonin. Immunoassay for 1,25-dihydroxyvitamin D3 suggested osteolysis was not operating via upregulation of this hormone's synthesis. Osteoclastogenesis was unaffected by indomethacin and only partially blocked by the IL-1 receptor antagonist. Neutralising antibodies to TNF and IL-6 inhibited osteoclastogenesis, as did 5-lipoxygenase (LOX) inhibition. The finding that 5-LOX activity could modulate osteolysis instigated an investigation into a wider role for 5-LOX products in osteolysis. This revealed the osteolytic activities of several inflammatory agents and hormones to be unaffected by 5-LOX inhibition, however osteolysis and osteoclastogenesis induced by A. actinomycetemcomitans LPS was. It was also demonstrated that the A. actinomycetemcomitans LPS was able to stimulate in vitro production of 5- LOX products. The LPSs from other oral bacteria also proved able to stimulate osteolysis and induce osteoclastogenesis by processes that were inhibited by 5-LOX inhibition. Attention then focused on the effects of A. actinomycetemcomitans LPS on the expression of LOXs and cyclooxygenases (COXs) in human osteoblasts. This LPS increased the synthesis of several LOX products, however 5-LOX mRNA expression was constituitive and was not altered by exposure to LPS, except with high doses and long exposure times when it was downregulated. COX-2 and 12-LOX mRNAs were found to be induced on exposure to the LPS, whilst neither 15-LOX nor COX-1 mRNAs were detected. Finally work moved to M. tuberculosis induced osteolysis. Of all the molecules tested only M. Tuberculosis cpn10 was found to be a potent stimulator of in vitro osteolysis and osteoclastogenesis, and to inhibit osteoblast proliferation. Studies with synthetic peptides of M. tuberculosis cpn10 revealed a single conformational unit, the flexible loop, encompassing its osteolytic activity.

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