**5.2.2 Proteasome inhibition and joint destruction**

Progressive destruction of bone and cartilage plays a pivotal role in the pathogenesis of RA. Effect of proteasome inhibitor MG132 on joint destruction was studied in AIA model [Ahmed et al., 2010]. The radiographic and histological analysis revealed that augmented cartilage and bone resorption, which is a characteristic feature of arthritis, was mitigated by the MG132 (Fig 8).

Bone resorption is a collective result of osteoclast stimulation and suppression of osteoblast precursors within the bone marrow. Previous studies have shown that NF-κB controls osteoclast activation through RANKL signalling [Soysa & Alles, 2009], while inhibition or deletion of RANKL prevents bone destruction [Zwerina et al., 2004; Pettit et al., 2001]. The protective effect of MG132 may be a consequence of with interfering osteoclast activation through the RANKL signalling pathway that is under control of NF-κB, or by enhancing the osteoblast activity. This assumption is supported by *in vitro* and *in vivo* studies indicating that the proteasome inhibitor bortezomib directly suppressed human osteoclast formation and promoted maturation of osteoblasts [Zangari et al., 2006; Mukharjee et al., 2008] and reduced joint destruction and preserved bone density in CIA mice [Lee et al., 2009].
