Modulation of bone morphogenetic protein signaling inhibits the onset and progression of ankylosing enthesitis
Rik J.U. Lories, Inge Derese, Frank P. Luyten
Rik J.U. Lories, Inge Derese, Frank P. Luyten
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Research Article Bone biology

Modulation of bone morphogenetic protein signaling inhibits the onset and progression of ankylosing enthesitis

Abstract

Joint ankylosis is a major cause of disability in the human spondyloarthropathies. Here we report that this process partially recapitulates embryonic endochondral bone formation in a spontaneous model of arthritis in DBA/1 mice. Bone morphogenetic protein (BMP) signaling appears to be a key molecular pathway involved in this pathological cascade. Systemic gene transfer of noggin, a BMP antagonist, is effective both as a preventive and a therapeutic strategy in the mouse model, mechanistically interfering with enthesial progenitor cell proliferation in early stages of the disease process. Immunohistochemical staining for phosphorylated smad1/5 in enthesial biopsies of patients with spondyloarthropathy reveals active BMP signaling in similar target cells. Our data suggest that BMP signaling is an attractive therapeutic target for interfering with structural changes in spondyloarthropathy either as an alternative or complementary approach to current antiinflammatory treatments.

Authors

Rik J.U. Lories, Inge Derese, Frank P. Luyten

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Noggin gene transfer prevents arthritis. (A) RT-PCR demonstrating enhanc...
Noggin gene transfer prevents arthritis. (A) RT-PCR demonstrating enhanced expression of noggin 72 hours after cDNA gene transfer (300 μg and 30 μg). Little endogenous noggin is found. The RT-negative control (RT-neg) obtained from muscle injected with 300 μg pcDNA3.1+noggin shows that the RNA extraction procedure successfully removed most of the potentially contaminating cDNA. (B) Real-time PCR analysis of noggin expression 72 hours after cDNA gene transfer. Mean ± SD from 2 samples. (C) Immunoprecipitation and Western blot demonstrating expression of noggin 72 hours after intramuscular plasmid cDNA gene transfer. A 26-kDa band corresponding to noggin was found in 2 different mice after gene transfer in the injected tibialis anterior muscle (right muscle, lanes 1 and 3) but was absent in contralateral control muscle (left muscle, lanes 2 and 4). Noggin was also detected in the serum of both noggin plasmid-injected mice (lanes 5 and 6) but not in control mice (lanes 7 and 8). Lane 8 shows a positive control using recombinant noggin-Fc. (D) Noggin gene transfer significantly reduced incidence of spontaneous arthritis as compared with empty vector–treated animals. *Gehan-Wilcoxon test, P < 0.05. (E) Noggin gene transfer (300 μg or 30 μg) significantly reduced severity of spontaneous arthritis as compared with that in empty vector–treated animals. *Mann-Whitney U test; P < 0.05 at week 25. (F) Noggin gene transfer significantly reduced time-integrated clinical severity, expressed as area under the curve, as compared with that in control animals. *Mann-Whitney U test; P < 0.05. (D and E) Data are shown as mean ± SEM; n = 8 or 9 mice per group.