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Abstract Number: 0966

Decoupling Inflammation and Bone Loss in Rheumatoid Arthritis via Schnurri-3

Zheni Stavre1, JungMin Kim2, Jae-Hyuck Shim2 and Ellen Gravallese3, 1University of Massachusetts Medical School-Rheumatology Division, Worcester, MA, 2University of Massachusetts Medical School, Worcester, MA, 3Brigham and Women's Hospital, Boston, MA

Meeting: ACR Convergence 2020

Keywords: bone biology, Mouse Models, RA, osteoblast, osteoporosis, rheumatoid arthritis

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Session Information

Date: Saturday, November 7, 2020

Title: RA – Animal Models (0965–0969)

Session Type: Abstract Session

Session Time: 5:00PM-5:50PM

Background/Purpose: Rheumatoid arthritis (RA) is a chronic inflammatory disease that leads to local and systemic bone loss. TNF is a key mediator of bone loss, not only through promotion of osteoclastogenesis, but also through inhibition of osteoblast function.  Schnurri3 (Shn3) is a large, intracellular zinc-finger adaptor protein and is a suppressor of osteoblast activity, as Shn3-deficient mice show a significant increase in bone mass due to augmentation of bone formation. We questioned whether targeting SHN3 in bone cells has therapeutic potential in RA-induced bone loss.

Methods: To investigate the effect of Shn3 global deletion on bone loss in arthritis, Shn3-deficient mice were crossed with SKG mice, a model of IL-17A and TNF-driven RA. SKG or Shn3-deficient-SKG mice were injected intraperitoneally with curdlan to synchronize arthritis onset. Mice were scored weekly for peripheral joint inflammation and sacrificed after 7 weeks of inflammation. Micro-computed tomography was used to evaluate joint erosions (ankles) and systemic bone loss (femurs). Histologic sections were scored for inflammation and bone erosion. To test the effect of deletion of Shn3 in osteoblast precursor cells in the setting of TNF overexpression, Shn3Prx1 mice were crossed with TNF-transgenic (TNF-tg) mice. Ankles and femurs were analyzed for inflammation and bone parameters as above. To further determine the effect of Shn3-deficient osteoblasts on bone in RA, the serum transfer arthritis (STA) model was employed in Shn3Prx1 mice sacrificed at peak inflammation. Mice were again similarly analyzed for inflammation and bone parameters.

Human bone marrow stromal cells (BMSCs) were infected with lentivirus (vector alone (control), SHN3 overexpression, control-shRNA, or SHN3 knockdown) and cultured under osteogenic conditions in the absence or presence of TNF plus IL-17A for 14 days. Mineralization activity was measured by alizarin red staining. Mouse COBs isolated from P5 WT and Shn3-deficient pups were cultured in the absence or presence of TNF plus IL-17A and mineralization was measured.

Results: Significant protection from joint erosion and systemic bone loss was noted in Shn3-deficient SKG and Shn3Prx1;TNF-tg mice, despite similar and ongoing inflammation.  In STA, Shn3-deficient osteoblasts were present at sites of erosion at the bone-pannus interface where typically few mature osteoblasts are present, indicating that Shn3-deficient osteoblasts continue to differentiate and populate eroded bone surfaces despite the presence of inflammation. In parallel with this observation, Shn3-deficiency in BMSCs and osteoblasts blocked the inhibitory activity of TNF/IL-17 for differentiation in vitro.

Conclusion: SHN3 acts downstream of and potentiates the negative effects on osteoblasts of TNF/IL-17A. Its inhibition allows for continued bone formation despite the presence of inflammation. Therefore, targeting this pathway provides a potential therapeutic strategy for RA-induced bone loss.


Disclosure: Z. Stavre, None; J. Kim, None; J. Shim, None; E. Gravallese, New England Journal of Medicine, 3, UpToDate, 7, Co-editor of the textbook Rheumatology, 7.

To cite this abstract in AMA style:

Stavre Z, Kim J, Shim J, Gravallese E. Decoupling Inflammation and Bone Loss in Rheumatoid Arthritis via Schnurri-3 [abstract]. Arthritis Rheumatol. 2020; 72 (suppl 10). https://acrabstracts.org/abstract/decoupling-inflammation-and-bone-loss-in-rheumatoid-arthritis-via-schnurri-3/. Accessed .
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