ECTS2014 Poster Presentations Osteoporosis: treatment (68 abstracts)
Faculty of Life Sciences, University of Manchester, Manchester, UK.
We have shown previously that TSG6 acts as an autocrine regulator of osteoclast activity in vitro, capable of inhibiting RANKL-mediated osteoclastic bone resorption with a similar potency to OPG1,2. Thus, the TSG6 protein has the potential to be developed as a novel treatment for osteoporosis, which is associated with excessive bone loss3.
The aim of this study was to determine the therapeutic potential of the isolated link module domain from human TSG6 (Link_TSG6; ~11 kDa), which, like the full-length protein, binds to RANKL1. Here we have demonstrated that Link_TSG6 inhibits lacunar resorption when osteoclast precursors are cultured on dentine slices in the presence of M-CSF/RANKL, with similar effects seen for both human and mouse cells (IC50=~1 nM). The finding that Link_TSG6 impairs F-actin ring formation (85% reduction at 0.85 nM) provides a likely mechanism for its anti-resorptive activity. We have also tested the efficacy of Link_TSG6 in vivo using the ovariectomised mouse model of post-menopausal osteoporosis; all work was carried out in accordance with UK Home Office regulations. Mice (ten per group) treated with Link_TSG6 (over a period of 4 weeks) showed a statistically significant reduction in serum levels of CTX-1 (a marker of bone breakdown) compared to vehicle controls. Furthermore, unlike zoledronate, Link_TSG6 did not reduce the levels of P1NP, a marker of bone formation. Importantly, analysis of femurs by micro-CT revealed a significant reduction in trabecular bone loss in Link_TSG6-treated animals.
Inhibition of bone resorption by Link_TSG6, in the absence of effects on bone formation, might represent an advantage compared to existing anti-resorptive treatments for osteoporosis, which significantly impair the bone-remodelling unit.
References
1. Mahoney DJ et al. J. Biol. Chem. 2008 283 2595225962.
2. Mahoney DJ et al. Arthritis Rheum. 2011 63 10341043.
3. Granted European patent; EP2001499 B1.