OP0012 MODULATION OF BONE MORPHOGENETIC PROTEIN SIGNALING IS INHIBITING ANKYLOSING ENTHESITIS IN A MOUSE MODEL OF SPONDYLOARTHROPATHY
R.J.U. Lories, I. Derese, K. De Vlam, F.P. Luyten. Belgium

Enthesitis is a hallmark feature of the human spondyloarthropathies (SpA). Spontaneous development of arthritis affecting toes and ankles of the hind paws occurs in male DBA/1 mice beginning at 15 weeks. The disease process is characterized by enthesial inflammation and cell proliferation followed by heterotopic cartilage and bone formation leading to the outgrowth of enthesophytes and eventually complete joint ankylosis. This sequence is strongly reminiscent of endochondral bone formation during embryonic development. The investigators studied the Bone Morphogenetic Protein (BMP) signaling pathway, which is critical during skeletal development in this model of Spondyloarthropathy.

Methods: Presence of BMP-2, BMP-6, BMP-7 and phosphorylated Smad 1/5/8 (pSmAD) (a downstream mediator of BMP signaling) in Ankylosing Enthesitis was studied by immunohistochemistry and immunofluorescence. Mice were treated with plasmid cDNA injections coding for mouse Noggin under the control of a strong cytomegalovirus promoter (pcDNA 3.1) at age week 12, week 15 and week 18. In additional experiments 300 g of mouse Noggin plasmid cDNA or empty vector control was injected after clinical signs had developed. Incidence, clinical severity and pathology scores were studied.

Results: In Ankylosing Enthesitis, BMP-2 is seen in early proliferating chondrogenic cells, BMP-7 is found in pre-hypertrophic chondrocytes while BMP-6 is largely restricted to hypertrophic chondrocytes. Repeated mouse Noggin cDNA injections significantly reduced incidence, clinical and pathological severity of Ankylosing Enthesitis. Noggin also reduced clinical and pathological severity when administered after the first symptoms occurred. Modulation of BMP signaling not only affected cartilage and bone formation but also influenced early inflammatory/proliferative stages of the disease.

Conclusion: Modulation of the BMP signaling pathway using over-expression of an extra-cellular antagonist has a profound impact on incidence and severity of Ankylosing Enthesitis in mice. These data suggest that BMP signaling is an important and new target for structure modifying therapies in SpA.

Editorial Comments: This is a novel study that promotes our understanding of the molecular mechanisms underlying the phenomena of enthesitis and ankylosis. A critical question is why the BMP pathway(s) is activated and what factor(s) sustain activation chronically. It will also be important to prove that these findings are relevant to the human spondyloarthropathies.

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