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Bone Abstracts (2014) 3 PP313 | DOI: 10.1530/boneabs.3.PP313

Osteoporosis: treatment

Preclinical evaluation of the link module from human TSG--6 as a novel anti-resorptive agent for postmenopausal osteoporosis

Ioannis Kanakis, Jenny Scott, Jennifer Thomson, Giles Hassall, Matthew Hardman, Caroline Milner & Anthony Day

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Faculty of Life Sciences, University of Manchester, Manchester, UK.


We have shown previously that TSG–6 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 TSG–6 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 TSG–6 (Link_TSG6; ~11 kDa), which, like the full-length protein, binds to RANKL1. Here we have demonstrated that Link_TSG–6 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_TSG–6 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_TSG–6 (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_TSG–6 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_TSG–6-treated animals.

Inhibition of bone resorption by Link_TSG–6, 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 25952–25962.

2. Mahoney DJ et al. Arthritis Rheum. 2011 63 1034–1043.

3. Granted European patent; EP2001499 B1.

Volume 3

European Calcified Tissue Society Congress 2014

Prague, Czech Republic
17 May 2014 - 20 May 2014

European Calcified Tissue Society 

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