Bone Abstracts

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 OPG^1,2. 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.