Inflammatory Pathways in Knee Osteoarthritis: Potential Targets for Treatment

Abstract

Osteoarthritis (OA) of the knee is a wide-spread, debilitating disease that is prominent in Western countries. It is associated with old age, obesity, and mechanical stress on the knee joint. By examining the recent literature on the effect of the anti-inflammatory prostaglandins 15d-PGJ2 and Δ12-PGJ2, we propose that new therapeutic agents for this disease could facilitate the transition from the COX-2-dependent pro-inflammatory synthesis of the prostaglandin PGE2 (catalyzed by mPGES-1), to the equally COX-2-dependent synthesis of the aforementioned anti-inflammatory prostaglandins. This transition could be instrumental in halting the breakdown of cartilage via matrix metalloproteinases (MMPs) and aggrecanases, as well as promoting the matrix regeneration and synthesis of cartilage by chondrocytes. Another desirable property of new OA therapeutics could involve the recruitment of mesenchymal stem cells to the damaged cartilage and bone, possibly resulting in the generation of chondrocytes, synoviocytes, and, in the case of bone, osteoblasts. Moreover, we propose that research promoting this transition from pro-inflammatory to anti-inflammatory prostaglandins could aid in the identification of new OA therapeutics.

Human C-reactive protein aggravates osteoarthritis development in mice on a high-fat diet

“…However, the increases in ARA and its metabolites point to an increased activation of PLA2. Combined enzymatic activities of PLA2 enzymes and cyclooxygenase (COX)-2 generate prostaglandins from ARA and members of this pathway have been implicated in OA pathogenesis 42,43 . Although sample volumes were insufficient to measure prostaglandin E 2 (PGE 2 ) levels, we did observe an increase in prostaglandin PGD 2 concentration over time e further corroborating increased PLA2 activity.…”

Benzoxime inhibits matrix metalloproteinase-13 activation and cartilage damage in osteoarthritis rats via inhibition of NF-κB pathway

“…The characteristic features of OA include knee joint edema, decomposition of cartilage, hyperplasia of synovium and degradation of sub-chondral bones [16]. Various cytokines such as nitric oxide, PG, interleukin-1β, tumor necrosis factor-α, interleukin-6 and interleukin-8 are expressed in higher proportions in the chondrocytes of OA patients [6,9]. Chondrocytes play an important role in the onset of pain during inflammation by activating the neurons [7,16].…”

“…In addition, benzoxime administration to OA rats significantly prevented knee edema, when compared to rats administered MIA alone. In OA patients benzoxime exhibits inhibitory effect on inflammation, and PGE2 upregulates degradation of cartilage by promoting the expressions of matrix metalloproteinases [9]. The level of matrix metalloproteinase-13 expression in OA patients is considered to be a reliable indicator of the extent of degradation of cartilage [19].…”

“…The expression of matrix metalloproteinases (which degrade cartilage tissues) is enhanced by prostaglandin E2 [9]. The currently-used nonsteroidal anti-inflammatory drugs for OA treatment are associated with development of complications, while steroidal agents do not show satisfactory results [9].…”

“…The currently-used nonsteroidal anti-inflammatory drugs for OA treatment are associated with development of complications, while steroidal agents do not show satisfactory results [9]. Thus, the need for identification of newer and more effective chemotherapeutic agents for OA has continued to be a challenge to clinicians.…”