Jenny Zhao, Presenter: Nothing to Disclose

S. Medicherla PhD, Abstract Co-Author: Nothing to Disclose

Jing Ma, Abstract Co-Author: Nothing to Disclose

R. Mangadu PhD, Abstract Co-Author: Nothing to Disclose

Qian Dong MD, Abstract Co-Author: Nothing to Disclose

Yebin Jiang MD, PhD, Abstract Co-Author: Nothing to Disclose

A. A. Protter PhD, Abstract Co-Author: Nothing to Disclose

et al, Abstract Co-Author: Nothing to Disclose

et al, Abstract Co-Author: Nothing to Disclose

Bone erosion with destruction of cartilage are poorly managed hallmarks of human rheumatoid arthritis (RA). p38α Mitogen-Activated Protein (MAP) kinase has been shown to regulate key pro-inflammatory pathways in RA, such as IL-1β,COX 2, and osteoclast differentiation. We evaluated whether a p38α MAP kinase inhibitor could modulate bone erosion and cartilage destruction in a mouse model of RA.

The animal model was induced in male DBA-1 Lac/J mice with bovine type II collagen immunized on day 1 and boosted on day 23. A baseline group (n=6) was sacrificed on day 32. Treatment of p38α MAP kinase inhibitor at 30 (n=12) or 90 (n=12) mg/kg/bid by oral gavage, or of vehicle (n=12), was initiated on day 33 for 20 days. A naïve group (n=5) consisted of intact animals without any injection. Clinical severity scores and paw swelling by plethysmography were monitored. Blood was tested for cartilage oligomeric matrix protein (COMP). The paws were examined by micro CT for erosion and bone microstructure and by histopathology. Bone erosion was scored on 3D reconstruction from micro CT images of isotropic resolution 16 micrometers, with 7 scales by 2 readers blinded to animal ID.

Significant bone erosions were noted in the animals of the baseline group. The score in the vehicle group was about 2-fold of the baseline, while the score in the treated groups was over 9-fold less than the vehicle and about 4-fold less than the baseline. 3D bone volume fraction and thickness were significantly greater in the treated than in the vehicle. Treated mice improved clinical severity scores and paw swelling, reduced mRNA levels in paw tissue for proinflammatory genes including IL-1β, IL-6, and COX-2. Histopathology demonstrated a reversal in bone and cartilage destruction, associated with reduced osteoclast number in the treated groups compared to the vehicle. Serum COMP levels, a marker of cartilage breakdown, were reduced in the treated compared to the vehicle.

In the model of inflammatory arthritis, p38α MAP kinase inhibition promotes bone erosion healing and reverses cartilage destruction.

Erosion healing is important for treatment of rheumatoid arthritis

Zhao, J, Medicherla, S, Ma, J, Mangadu, R, Dong, Q, Jiang, Y, Protter, A, et al, , et al, , Erosion Healing in Inflammatory Arthritis Treated with A Selective p38a Mitogen-activated Protein Kinase Inhibitor.  Radiological Society of North America 2007 Scientific Assembly and Annual Meeting, November 25 - November 30, 2007 ,Chicago IL. http://archive.rsna.org/2007/5016038.html