Oral Presentation Annual Meetings of the Endocrine Society of Australia and Society for Reproductive Biology and Australia and New Zealand Bone and Mineral Society 2016

Shifting the balance towards STAT3: identification of a new anabolic pathway for bone (#16)

Emma C Walker 1 , Rachelle W Johnson 1 , Yifang Hu 2 , Holly J Brennan 1 , Ingrid J Poulton 1 , Brendan J Jenkins 3 , Gordon K Smyth 2 , Nicos A Nicola 2 , Natalie A Sims 1
  1. St Vincent's Institute, Fitzroy, VIC, Australia
  2. Walter and Eliza Hall Institute, Parkville, VIC, Australia
  3. The Hudson Institute, Clayton, VIC, Australia

Oncostatin M (OSM) is a paracrine factor expressed by osteoblasts, osteocytes and macrophages that stimulates bone formation by inibiting osteocytic production of sclerostin. OSM also stimulates osteoclastogenesis by promoting osteoblastic expression of RANKL. These actions are required for normal bone mass in juvenile and adult skeletons and for normal skeletal response to parathyroid hormone (PTH). Surprisingly, in the absence of the OSM receptor (OSMR), mouse OSM (mOSM) can signal through the leukemia inhibitor factor (LIF) receptor (LIFR) to suppress sclerostin and stimulate bone formation. Unlike canonical LIFR signalling induced by LIF, when mOSM acts through mLIFR (mOSM:LIFR), it does not significantly stimulate RANKL production, suggesting it may activate a novel pathway that could increase bone mass by stimulating bone formation without promoting bone resorption.

To identify the unique downstream targets of mOSM:mLIFR, microarray expression profiling was carried out in LIF- and mOSM-treated wildtype and Osmr-/- primary osteocyte-like cells. The genes regulated by mOSM:LIFR comprised a subset of those regulated by canonical LIFR signalling. The mOSM:LIFR-responsive gene subset included STAT3 target genes (e.g. Socs3, Bcl3, Cxcl1 and Mmp13) but lacked STAT1 target genes induced by canonical LIFR signalling (e.g. Socs1, Mx2, Cxcl9, Ccl2). Western blotting confirmed that while canonical LIFR signalling induced phosphorylation of both STAT3 and STAT1, mOSM:LIFR phosphorylated only STAT3 and not STAT1.

To determine whether favouring STAT3 over STAT1 signalling could protect skeletal mass we used a previously described mouse model of osteopenia caused by hyperactivation of STAT1/3 signalling downstream of the receptor gp130 (gp130Y757F/Y757F). In these mice STAT1 deletion rescued the osteopenic phenotype, indicating a beneficial effect of promoting STAT3 signalling over STAT1 downstream of gp130. This suggests that promoting STAT3 signalling over STAT1 may provide a therapeutic benefit in low bone mass conditions.