Basic nutritional investigationInhibition of cartilage degradation and suppression of PGE2 and MMPs expression by pomegranate fruit extract in a model of posttraumatic osteoarthritis
Introduction
Osteoarthritis (OA) is the most common form of arthritis worldwide and a major cause of morbidity, physical limitation, disability, and socioeconomic burden [1], [2], [3]. Although cartilage matrix breakdown is the major characteristic of OA, the joint pathology also involves synovial membrane and subchondral bone changes [4]. OA is believed to be a consequence of mechanical and biochemical events that result in an imbalance between the synthesis and degradation of articular cartilage matrix consisting of proteoglycans (PGs), collagens (types II, IX, XI, and X, and others), and water [4], [5], [6]. Evidence now firmly supports the view that inflammation not only contributes to the development of symptoms but also plays a role in the progression of structural damage including cartilage degradation [7], [8], [9]. Excessive production of cartilage degrading enzymes such as the aggrecanases (ADAMTS-4 and -5) and matrix metalloproteinases (MMPs), which are the key player in degradation of aggrecan (ACAN) and collagen type II (COL2A1) has been shown in OA joints [10], [11], [12]. Studies have correlated increased chondrocyte apoptosis with OA severity in humans and animal models [13], [14], [15]. Moreover, cell death positively correlates with matrix degradation and calcification [16], [17]. In this regard, increased caspase-3 expression has been found to correlate with reduced cell density in human OA cartilage [18], whereas inhibition of apoptosis using caspase inhibitors reduced the severity of cartilage lesions in experimental OA [19]. Currently, goals of OA management include controlling pain, maintaining and improving the range of movement and stability of affected joints, and limiting functional impairment [20], [21]. Because of the association of severe adverse events with the use of nonsteroidal antiinflammatory drugs (NSAIDs), at least one-third of older adults use some form of complementary and alternative medicine for pain [22], [23].
Pomegranate (Punicagranatum L., Punicaceae) is an ancient fruit that has not changed much throughout human history. The fruit itself is a rich source of two types of polyphenolic compounds: anthocyanins (such as delphinidin, cyanidin, and pelargonidin), which give the fruit and juice its red color, and hydrolyzable tannins (such as punicalin, pedunculagin, punicalagin, gallagic, and ellagic acid), which account for 92% of the antioxidant activity of the whole fruit [24], [25]. Studies have reported that the antioxidant capacity of pomegranate juice is three times that of the popular antioxidant-containing beverages such as red wine and green tea, presumably due to the presence of hydrolyzable tannins in the rind, along with anthocyanins and ellagic acid derivatives [25], [26], [27]. In a comparative analysis, anthocyanins from pomegranate were found to possess higher antioxidant activity than vitamin E (α-tocopherol), ascorbic acid and 3-carotene [26]. Pomegranate extract has been shown to protect from NSAID- and ethanol-induced gastric ulceration [28]. The whole-fruit extract is widely used in several traditional medicinal systems for the treatment of inflammation and pain in arthritis and other diseases [22]. The family of phytochemicals found in pomegranate fruit act together with greater potency than any single constituent alone [29]. Previously we have shown that a standardized pomegranate fruit extract (PFE) inhibit the production of MMPs via blocking the activation of p38-mitogen-activated protein kinase (MAPK) and the transcription factor nuclear factor (NF)-κB in OA chondrocytes [30]. Other studies found that bioavailable metabolites of PFE inhibited cyclooxygenase (COX)-2 activity in OA chondrocytes [31], and that consumption of PFE suppressed the inflammation and joint destruction in collagen-induced arthritis (CIA) mouse model [32]. also It has also been demonstrated that pretreatment of OA chondrocytes with PFE inhibited the interleukin (IL)-1 β-induced activation of the upstream kinase MKK3, resulting in the inhibition of p38 α-MAPK isoform and the activation and DNA-binding activity of the transcription factor RUNX-2 [33]. In the present study we examined the cartilage and chondroprotective effects of oral consumption of PFE in vivo using the rabbit model of posttraumatic OA in which the disease is induced through anterior cruciate ligament transection (ACLT) [34], [35]. Results from the present study demonstrated that in rabbits that orally consumed PFE, there was less cartilage damage and fewer apoptotic chondrocytes in the joints with surgically induced OA. Expression of IL-6, MMPs and prostaglandin (PG)E2 was also reduced, whereas the expression of ACAN and COL2A1 was high in the OA joints of rabbits fed PFE. Inhibition of IL-1 β-induced IL-6 and MMPs expression, MMP-13 activity and PGE2 production with an increase in COL2A1 level was observed by PFE pretreatment in rabbit articular chondrocytes. These data suggests that consumption of PFE may be chondroprotective and may be used as an adjunct therapy for the management of OA.
Section snippets
ACLT surgery to induce OA in rabbits
The model used to study the effects of PFE consumption on the development of OA was the rabbit ACLT model as it produces a reliable and reproducible degradation of articular cartilage [36]. All animal studies were approved by the IACUC of the Case Western Reserve University (CWRU), Cleveland, Ohio (protocol no. 2009-0209) and the IACUC of the Northeast Ohio Medical University (Protocol #13-002). Animal surgeries and sacrifice were carried out using the facilities of the Animal Resource Center
Effect of PFE administration on macroscopic and histologic parameters
Postmortem inspection of rabbit knees revealed that ACLT was complete in all rabbits included in the study. In the right femorotibial joints subjected to sham surgery, the articular cartilage macroscopic grades were normal or scarcely perceptible India ink uptake and no cartilage erosions were observed in any of the joint compartments (Supplementary Fig. 1), whereas the induced OA lesions (erosion of articular cartilage) were focal in joints in which ACLT was performed. In animals that were fed
Discussion
The present study was carried out to determine the effect of oral administration of PFE on cartilage degeneration in a rabbit model of posttraumatic OA. In this model, oral administration of PFE was markedly effective against joint destruction. The histologic findings were informative with respect to the effects of PFE on OA cartilage structural changes. In fact, rabbits in both groups that were fed PFE exhibited a significant decrease in the markers of cartilage matrix damage, such as loss of
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This work was supported in part by grants from National Institute of Health grants (RO1 AT-003267; RO1-AT-005520, R21-AT504615) and funds from the Northeast Ohio Medical University. TMH conceived the study. NA and TMH were responsible for its design and coordination of the data acquisition and analyses, interpretation of the data, manuscript preparation, and statistical analyses. NA performed the ACLT surgeries. NMK set up the rabbit chondrocyte cultures, performed the MMPs activity assay and enzyme-linked immunosorbent assay (ELISA), data acquisition and interpretation. OA performed the PGE2 ELISA and data acquisition and interpretation. All authors approved the final version of the manuscript. The authors have no conflicts of interest to declare.