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.

Cell-specific effects of TNF-α and IL-1β on alkaline phosphatase: implication for syndesmophyte formation and vascular calcification

“…The putative interest of targeting BMPs in AS has been suggested by Lories and collaborators, who showed that overexpression of noggin, a BMP antagonist with broad BMP ligand interaction, inhibits both the onset and severity of disease in the DBA/1 model of spondyloarthropathy, in a preventive and therapeutic strategy. 39 Interestingly enough, our histological studies revealed the presence of calcified fibro-cartilage surrounding the characteristic fibro-chondrocyte rows (Figure 2c), which therefore demonstrates that mineralization of a pre-existing ECM is an early event in the bone formation proceeding from the calcaneus into the Achilles tendon. Consequently, TNAP expression by entheseal cells is likely a key event that initiates ossification (Figure 2).…”

GP130 cytokines and bone remodelling in health and disease

“…In mouse models of inflammatory arthritis that share features with SpAs, formation of new bone in the form of osteophytes and subsequent ankylosis has been linked to activation of the BMP (89) and Wnt signalling pathways (90). Recently downregulation of the Wnt signalling antagonist sclerostin in osteocytes has been noted at sites adjacent to syndesmophyte formation in retrieved tissues from ankylosing spondylitis patients (91) suggesting that this may be one mechanism by which bone formation is induced in the context of inflammation and mechanical strain at the entheseal site.…”

How antirheumatic drugs protect joints from damage in rheumatoid arthritis

“…Extensive bone responses to these erosive lesions are usually lacking in RA, which is due to an impaired formation of osteoblasts, which could potentially refill these lesions with new bone. On a molecular level, this absence of skeletal response in RA is most likely based on the induction of negative regulators of osteoblasts such as Dkk-1 or noggin, which are expressed by the inflammatory tissue and inhibit bone formation (22,23).…”