Specific blockade of Interleukin-6 trans-signalling prevents ovariectomy-induced trabecular bone loss — ASN Events
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  3. Specific blockade of Interleukin-6 trans-signalling prevents ovariectomy-induced trabecular bone loss

Specific blockade of Interleukin-6 trans-signalling prevents ovariectomy-induced trabecular bone loss (#42)

Leah Lazzaro 1 , Ingrid J Poulton 1 , Brett A Tonkin 1 , Narelle E McGregor 1 , Walter Ferlin 2 , Natalie A Sims 1
  1. St Vincent's Institute, Fitzroy, VIC, Australia
  2. NovImmune SA, Plan-les-Ouates, Switzerland

Interleukin 6 (IL-6) stimulates bone resorption, and has been implicated in the bone loss caused by estrogen deficiency. IL-6 signals through two different pathways: classic (cis) signaling utilizes a membrane bound IL-6 receptor (IL-6R), while IL-6 trans-signalling occurs through a soluble form of the same receptor (sIL-6R); it is not known which of these two pathways mediated ovariectomy-induced bone loss. Since both IL-6 and sIL-6R are systemically elevated in estrogen deficiency in humans and mice, we sought to determine whether estrogen deficiency-associated bone loss can be inhibited by blockade of IL-6 trans-signalling.

Mice were sham operated or ovariectomized (OVX) at 16 weeks of age, and left untreated, or treated with twice-weekly intravenous injection of 25F10, an antibody shown to specifically block IL-6 trans-signalling, or IgG control until 20 weeks of age. Compared to SHAM controls, both OVX and OVX+IgG mice demonstrated a significant (25%) reduction in tibial trabecular bone volume (BV/TV) and number (TbN). This bone loss was not observed in OVX+25F10 mice. Tibial histomorphometry of the secondary spongiosa showed that 25F10 treatment prevented the significant increase in osteoclast surface associated with ovariectomy, but did not reduce osteoblast numbers. In contrast to its protective effect in trabecular bone, 25F10 treatment did not prevent the reduction in cortical thickness or increase in marrow area associated with ovariectomy. Consistent with a role for IL-6 trans-signaling in trabecular bone only, ADAM17, a sheddase that induces sIL-6R release, was detected by immunohistochemistry in osteocytes and osteoblasts in trabecular, but not cortical, bone.

In conclusion, the increased osteoclast formation and trabecular bone loss associated with estrogen-deficiency is mediated, at least in part, by IL-6 trans-signalling, but cortical bone loss and increased bone formation are independent of this pathway; this difference may be explained by local differences in sIL-6R release by osteoblasts and osteocytes.