Soluble Interleukin-6 receptor released by osteocytes promotes bone formation by <em>trans-</em>signaling — ASN Events
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  3. Soluble Interleukin-6 receptor released by osteocytes promotes bone formation by trans-signaling

Soluble Interleukin-6 receptor released by osteocytes promotes bone formation by trans-signaling (#71)

Narelle E McGregor 1 , Melissa Murat 1 , Emma C Walker 1 , Brett A Tonkin 1 , Jonathan H Gooi 2 , Patricia WM Ho 1 , Jeevithan Elango 1 , T. John Martin , Natalie Sims 1
  1. St Vincent's Institute, Fitzroy, VIC, Australia
  2. Department of Medicine at St. Vincent's Hospital, The University of Melbourne, Melbourne, VIC, Australia

Interleukin 6 (IL-6) acts through two receptor-mediated pathways (cis and trans). Cis-signalling occurs in cells expressing IL-6R, while trans-signalling uses a soluble IL-6R (sIL-6R), and can occur in non-receptor-bearing cells, particularly in inflammatory conditions when circulating sIL-6R levels are high. The role of IL-6 in bone is poorly understood, and although osteoblasts express IL-6R, their support of osteoclast formation in vitro requires addition of sIL-6R.

 

Undifferentiated Ocy454 osteocytes and Kusa 4b10 stromal cells expressed IL-6R mRNA, but did not release sIL-6R protein (ELISA). As these cells differentiated secreted sIL-6R levels increased, reaching 150pg/ml at the stage of sclerostin expression, indicating that osteocytes are a source of sIL-6R. As in osteoblasts, IL-6+sIL-R stimulated RANKL mRNA levels in Ocy454 cells, but unlike osteoblasts, Ocy454 osteocytes did not support osteoclast formation in co-culture.  

 

Sclerostin mRNA was suppressed by IL-6+sIL-6R treatment of Ocy454 cells, suggesting it might stimulate bone formation. Indeed, when C57BL/6 mice were treated with either IL-6+sIL-6R or hyper-IL-6 (synthetic IL-6 covalently linked to sIL-6R, capable only of trans-signalling) calvarial thickness was increased by 17±6μm (13%) and 24±6μm (18%) respectively (p<0.05); this was not observed with IL-6 alone. IL-6 therefore both stimulates osteoclastogenesis and bone formation through trans-signalling.

 

To determine the role of trans-signalling in vivo, we assessed mice genetically modified to produce circulating sgp130-Fc, a stable gp130 co-receptor homodimer which, when expressed at low levels, specifically blocks trans-signalling. No significant alterations in bone mass or mechanical strength by 3 point bending were detected. This indicates that trans-signalling is not required for normal bone mass.

 

In conclusion, osteocytes are a local source of sIL-6R, and although IL-6 stimulates bone formation through trans-signaling, it is not required for normal trabecular bone mass, suggesting that therapeutic trans-signalling inhibitors are unlikely to have a detrimental effect on bone formation.