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Abstract Number: 1824

Osteoclast Derived-Autotaxin, a Distinguishing Factor for Inflammatory Bone Loss

Olivier Peyruchaud1, Sacha Flammier1, Fanny Bourguillault1, Francois Duboeuf1, Gabor Tigyi2, Irma Machuca-Gayet1 and Fabienne Coury1, 1INSERM UMR1033, Lyon, France, 2Department of Physiology, University of Tennessee, Memphis, TN

Meeting: 2018 ACR/ARHP Annual Meeting

Keywords: osteoclasts and rheumatoid arthritis (RA)

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Session Information

Date: Monday, October 22, 2018

Session Title: 4M085 ACR Abstract: RA–Animal Models (1822–1827)

Session Type: ACR Concurrent Abstract Session

Session Time: 2:30PM-4:00PM

Background/Purpose:

Rheumatoid arthritis (RA) patients in sustained clinical remission or low disease activity may continue to accrue periarticular bone erosions despite control of inflammation. Osteoclasts are responsible for bone erosions and systemic bone loss in RA. However current anti-resorptive drugs are suboptimal in RA because they could lead to issues by shutting down physiologic remodeling in long term treatment supporting the need for alternative therapies. Autotaxin (ATX) is a secreted lysophospholipase D converting lysophosphatidylcholine into lysophosphatidic acid. ATX is upregulated in the synovial liquid of patients with RA and contributes to synovial inflammation. However, ATX role in bone resorption is totally unknown.

Methods:

ATX was targeted by conditional genetic ablation in osteoclasts (ΔATXCtsk mice) and by treatment with anti-ATX drug (BMP22). Arthritic and erosive diseases were studied in arthritis models using human tumor necrosis factor transgenic (hTNF+/-) mice and K/BxN serum-treated mice. Systemic bone loss was in addition analysed after ovariectomy (OVX) and in the Lipopolysaccharide (LPS)-induced inflammation model. Joint inflammation and osteoclasts were assessed by histology and bone mass and bone erosion by microcomputed tomography (micro-CT). ATX expression was assessed using RT-qPCR and Western blot. The role of ATX on osteoclastogenesis and osteoclast activity were analysed by murine and human assays.

Results:

Here, we found that ATX was up regulated during the course of osteoclastogenesis and LPS or TNF applied to mature osteoclasts further enhanced ATX expression. In vitro osteoclast-derived ATX was necessary for bone resorption activity that was blocked by pharmacological ATX inhibitors (PF-8380, BMP22). LPS injections induced a 43 % decrease of the trabecular BV/TV in control mice but had no impact on bone in ΔATXCtsk mice. The challenge with K/BxN serum transfer which induces severe arthritis revealed that ΔATXCtsk mice were protected from systemic bone loss, and displayed almost no bone erosion. Intriguingly, in a non-inflammatory bone loss condition as observed in mice after OVX, ΔATXCtsk and control mice revealed similar impact on bone 4 weeks post-OVX with a 30% decrease in BV/TV. As supported by an absence of bone phenotype at steady state on ΔATXCtsk mice, these results indicate that osteoclast-derived ATX might be dispensable for osteoclast function under non-inflammatory conditions. By using a pharmacological approach on a second inflammatory mouse model exploiting hTNF mice, we found that albeit inefficient on synovitis, BMP22 induced a 28% increase in BV/TV and a 50% decrease in the extent of bone erosion (BS/BV).

Conclusion:

These results establish that ATX is a new factor produced by osteoclasts that controls inflammation-induced bone loss without interfering with osteoclast function in non-inflammatory conditions. ATX might be a promising therapeutic target for the prevention of bone erosion occurrence in RA.


Disclosure: O. Peyruchaud, None; S. Flammier, None; F. Bourguillault, None; F. Duboeuf, None; G. Tigyi, None; I. Machuca-Gayet, None; F. Coury, Pfizer, Inc.; Abbvie; Novartis; MSD;, 5.

To cite this abstract in AMA style:

Peyruchaud O, Flammier S, Bourguillault F, Duboeuf F, Tigyi G, Machuca-Gayet I, Coury F. Osteoclast Derived-Autotaxin, a Distinguishing Factor for Inflammatory Bone Loss [abstract]. Arthritis Rheumatol. 2018; 70 (suppl 10). https://acrabstracts.org/abstract/osteoclast-derived-autotaxin-a-distinguishing-factor-for-inflammatory-bone-loss/. Accessed January 17, 2021.
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