**2.5 Osteoclasts**

Enhanced osteoclast activity triggered by disproportionate ratio of Osteoprotegerin (OPG) and receptor activator of nuclear-factor kappa-beta ligand (RANKL) are critical factors for RA progression. When RANKL is overexpressed by activated macrophages, osteoblasts and lymphocytes, it stimulates an imbalance between osteoclast multiplication and anomalous activation triggered by the binding of RANKL to RANK on the mature osteoclasts and on the cell-membranes of precursor cells of osteoclast [21]. In addition, MMP-9 and MMP-14 secreted by the osteoblasts, triggers matrix degradation in cartilage, formation of pannus, and osteoclast migration to surface of the bone. Osteoclasts significantly cause erosion of subchondral bone, articular cartilage, and the synovium.

## **2.6 Enzymes and other effector molecules**

MMPs are the enzymes that irreversibly cause extracellular matrix (ECM) degradation, and slow-destruction of cartilage and bone in diseased joints. MMPs are zinc-dependent endopeptidases that are categorized into five sub-classes: i) gelatinases (MMP-2 and 9), ii) collagenases (MMP-1, −8 and 13), iii) stromelysins (MMP-3, −10 and − 11), iv) matrilysins (MMP-7 and -26) and v) membrane-type MMPs (MMP-14 to −17, −24 and − 25) [22, 23]. MMP-1, 2, 3, and 9 have been directly implicated in RA progression [24]. MMPs, in combination with lipases and esterases, accelerate degradation of ECM, articular cartilage and surface of the subchondral bone [25]. Ever-increasing emerging targets including these enzymes provide more options for anti-arthritic therapy with the help of targeted SDDS for RA.

*Smart Drug-Delivery Systems in the Treatment of Rheumatoid Arthritis: Current, Future… DOI: http://dx.doi.org/10.5772/intechopen.99641*
