Imatinib mesylate inhibits osteoclastogenesis and joint destruction in rats with collagen-induced arthritis (CIA)

Abstract

Macrophage colony-stimulating factor (M-CSF) is a key factor for osteoclastogenesis at the bone-pannus interface in patients with rheumatoid arthritis as well as a receptor activator of NF-kappaB ligand (RANKL). Imatinib mesylate inhibits the phosphorylation of c-fms, a receptor for M-CSF. The present study investigates the effect of imatinib mesylate on joint destruction in rats with collagen-induced arthritis (CIA) and on osteoclastogenesis in vitro. Imatinib mesylate (50 or 150 mg/kg), dexamethasone, or vehicle was administered daily to CIA rats for 4 weeks from the onset of arthritis. Hind-paw swelling and body weight were measured weekly. At weeks 2 and 4, the metatarsophalangeal (MTP) joints and the ankle and subtalar joints were radiographically and histologically assessed. The effect of imatinib mesylate on osteoclast formation from rat bone marrow cells with M-CSF and soluble RANKL (sRANKL) in vitro was also examined. Radiographic assessment showed that 150 mg/kg imatinib mesylate suppressed the destruction of the MTP and the ankle and subtalar joints at week 2, and MTP joint destruction at week 4 in CIA rats, although hind-paw swelling was not suppressed. The number of TRAP-positive cells at the bone-pannus interface was significantly reduced in the group administered with 150 mg/kg imatinib mesylate compared with that given vehicle at week 4. Imatinib mesylate dose-dependently inhibited the proliferation of M-CSF-dependent osteoclast precursor cells in vitro as well as osteoclast formation induced by M-CSF and sRANKL. These findings suggest that imatinib mesylate could prevent joint destruction in patients with rheumatoid arthritis.

Imatinib mesylate reduces production of extracellular matrix and prevents development of experimental dermal fibrosis

“…The potential future role of imatinib mesylate as a novel therapeutic option for rheumatic diseases is highlighted by a recent study demonstrating its ability to inhibit osteoclast formation and reduce joint destruction in rats with collagen-induced arthritis (34). Imatinib mesylate inhibited, in a dose-dependent manner, the proliferation of osteoclast precursor cells as well as the formation of osteoclasts.…”

Effects of tyrosine kinase inhibition on bone metabolism: untargeted consequences of targeted therapies

“…There is now clear in vitro and in vivo evidence that imatinib decreases the ability of osteoclasts to resorb bone. The in vitro evidence for an anti-osteoclastic activity of imatinib ranges from murine systems showing a decrease in osteoclastic precursors of the hematopoietic stem cell lineage to decreased osteoclastogenesis in human CD14C peripheral mononuclear cells (Ando et al 2006, El Hajj Dib et al 2006. More recently, the first evidence of decreased osteoclast number and activity in human bone of imatinib-treated patients was shown (Vandyke et al 2012).…”

Selective tyrosine kinase inhibition by imatinib mesylate for the treatment of autoimmune arthritis

“…Ando and colleagues observed that, after the development of clinical arthritis, rats treated with imatinib experienced a reduction in joint destruction and pannus formation (54).…”