Omega-3 Fatty Acids Mitigate Obesity-induced Osteoarthritis And Accelerate Wound Repair

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1 Omega-3 Fatty Acids Mitigate Obesity-induced Osteoarthritis And Accelerate Wound Repair Chia-Lung Wu, MS, Deeptee Jain, MD, Jenna McNeill, BS, Dianne Little, BVSc, PhD, John Anderson, MD, Janet Huebner, MS, Ramona Rodriguiz, PhD, William Wetsel, PhD, Virginia Kraus, MD, PhD, Farshid Guilak, PhD. Duke University, Durham, NC, USA. Disclosures: C. Wu: None. D. Jain: None. J. McNeill: None. D. Little: 3B; Cytex Therapeutics Inc. J. Anderson: None. J. Huebner: None. R. Rodriguiz: None. W. Wetsel: None. V. Kraus: None. F. Guilak: 3A; Cytex Therapeutics Inc. 4; Cytex Therapeutics Inc. 7; Elsevier Ltd.. Introduction: Obesity is a primary risk factor for osteoarthritis (OA) and impaired wound healing. However, mechanical factors alone, such as increased body weight, do not account for the increased incidence of OA in the non-weight bearing joints such as the hand (1), and increasing evidence suggests that dietary content such as fatty acids (FAs) within a high-fat (HF) diet can play a vital role in tissue inflammation. Western diets are rich in inflammatory saturated fatty acids (SFA) and contain a high ratio of ω- 6 to ω-3 FAs. Previous studies have shown that a SFA-rich HF diet can increase OA severity (2), while supplementation with antiinflammatory ω-3 FAs in a regular diet can reduce OA (3). However, it is still unclear whether ω-3 can provide a protective effect against OA and promote wound healing in the context of joint injury or HF feeding. The objective of this study was to elucidate the associations among OA, wound healing, body weight, and FAs using an obese mouse model of meniscal injury (DMM), as measured by histologic changes, OA biomarkers, and measures of pain and motor function. Methods: Male C57BL/6J mice were fed a low fat (Control, 10%) or one of the three HF (60%) diets: SFA, ω6, or ω3-rich HF diet for 24 weeks (n = /group). The body fat content, bone mineral density (BMD), serum biomarkers, and activity measurements were measured at various timepoints. At 16 weeks of age, mice underwent surgery for destabilization of the medial meniscus (DMM) to induce knee OA (4) and ear punches for studying wound healing. Upon sacrifice, visceral fat was isolated for gene expression. Joint were analyzed using microct. OA, joint inflammation, and healing capacity were determined by histologic grading. Multivariable analyses were performed to evaluate the associations among metabolic factors, weight, wound healing and OA. Results: Body mass: The SFA and ω-6 mice were heavier than other mice (Fig 1A). Area under the weight versus time curve (AUC) represents the influence of weight on joints over time (Fig 1B). HF mice had higher AUC. The SFA and ω-6 mice exhibited increased percentages of body fat and epididymal fat but decreased body BMD (Fig 1, C-E). Gene expression and macrophages (Mϕ) in fat: HF rich in SFA or ω-6 increased Mϕ infiltration into visceral fat (Fig 1F). Gene expression confirmed that SFA and ω-6 exhibited a trend toward increasing expression of inflammatory cytokines in fat (Fig 1G).

$Bone remodeling: 3D images of joints (Fig 2A). Diet significantly affected the cancellous bone fraction (BV/TV) of the femoral condyle (FC) (Fig 2B).$

2 Bone remodeling: 3D images of joints (Fig 2A). Diet significantly affected the cancellous bone fraction (BV/TV) of the femoral condyle (FC) (Fig 2B). Surgery, but not diet, significantly decreased the BMD of the FC (Fig 2C-D). At the tibial epiphysis (TP), surgery significantly increased BV. ω-6 and SFA mice had higher BV of heterotopic ossification (Fig 2E).

OA and osteophytes: Cartilage loss was observed in SFA and ω-6 mice, while control and ω-3 mice only exhibited moderate loss of GAGs and low osteophyte counts (Fig 3, A-B).

3 OA and osteophytes: Cartilage loss was observed in SFA and ω-6 mice, while control and ω-3 mice only exhibited moderate loss of GAGs and low osteophyte counts (Fig 3, A-B). OA score was positively associated with osteophyte severity (Fig 3C). Synovitis: Increased synovitis was present in both SFA and ω-6, characterized by increased Mϕ, while ω-3 mitigated synovial inflammation (Fig 3D). The ω-6 mice had the highest synovitis and Mϕ score (Fig 3E).

4 Serum biomarker: SFA and ω-6 mice had higher concentrations of insulin, leptin, and resistin compared to the other groups, while ω-3 mice exhibited low adiponectin levels (Fig 4).

5 Regression analyses: OA was positively associated with diet and metabolic factors, leptin and resistin, but not with mechanical factor such as the weight versus time AUC values (Table 1).

6 Activity levels: Diet did not significantly affect spontaneous locomotion, rotarod or grip strength (Fig 5, A-C). Hotplate limb withdrawal threshold did not significantly differ among the mice. At 24 weeks, a significant difference in tail-flick was observed between ω-6 and SFA mice, but not among other diet groups (Fig 5, D-E).

Ear wound healing: ω-3 mice had enhanced wound healing and epithelial thickness with numerous neo-cartilage islands compared to the mice fed other diets (Fig 6, A-E).

7 Ear wound healing: ω-3 mice had enhanced wound healing and epithelial thickness with numerous neo-cartilage islands compared to the mice fed other diets (Fig 6, A-E). No difference in cell proliferation was observed with Ki67 IHC (Fig 6F) but ω-3 mice showed less collagen type I deposition in the repaired matrix, suggesting less scar formation (Fig 6G). Wound size showed a trend toward positive association with OA score (Fig 6H).

Discussion: SFAs and ω-6 FAs significantly increased OA severity following joint injury, while ω-3 FAs mitigated joint degeneration associated with injury and a high fat diet.

8 Discussion: SFAs and ω-6 FAs significantly increased OA severity following joint injury, while ω-3 FAs mitigated joint degeneration associated with injury and a high fat diet. SFAs can increase systemic inflammation through the recruitment of macrophages into fat (5). Our results also showed that SFAs increased the expression of inflammatory cytokines. The beneficial role of ω-3 FAs in OA has been reported in various animal models (3), although most of these studies supplemented lean diets with ω-3 FAs. In this study, we showed that even small amounts of ω-3 FAs supplemented in a HF diet (only a 6.5 kcal% increase in the energy provided by ω-3 as compared to that in ω-6 diet), provided a protective effect on injury induced OA and synovitis associated with high-fat feeding. A recent report demonstrated that ω-3 significantly reduced loss of GAGs in cartilage explants (6). ω-3 mice also had high levels of serum adiponectin, which may reduce systemic inflammation through increasing insulin sensitivity (7). Despite having higher body weight (AUC values), ω-3 mice did not exhibit worse OA than the control mice, suggesting that factors other than weight are involved in OA. Regression analyses indicated that OA was associated with diet, adipokines, and inflammatory cytokines, but not with body mass, which emphasizes the significance of biochemical factors in OA. Another significant finding was that ω-3 mice showed superior ear wound healing capacity as well as less scar formation.

9 Whether ω-3 facilitates wound healing is still controversial (8). ω-3 seems to delay wound closure by interrupting the inflammatory phase in lean healthy animals (9). However, in models that involve chronic inflammation, such as obesity, ω-3 may reduce unnecessary inflammation and thereby provide beneficial effects (10). Our results, that ear healing capacity trends toward association with OA, supports a recent study demonstrating that ear wound and articular cartilage regeneration may share common heritable genetic bases (11). SFA and ω-6 mice showed increased heterotopic ossification in the tendon following DMM. While the mechanisms involved in this process are not fully understood, ω-6 can increase PGE2 production (12), which in turn can enhance osteogenic differentiation of tendon stem cells (13). HF feeding did not alter spontaneous locomotion, suggesting that weight gain is not caused by less energy expenditure on spontaneous activity. Notably, locomotion did not correlate with OA in our model, which is in accordance with numerous longitudinal studies showing that recreational physical activities do not contribute to knee OA in either normal or overweight individuals (14). Significance: This study extends our understanding of the roles of dietary FAs and their lipid mediators in OA pathogenesis and wound healing, and may provide evidence on which to base new dietary interventions for obese patients. Acknowledgments: We thank Stephen Johnson for technical assistance. Supported by NIH AR50245, AG15768, AR48852, AR48182, AR59784, Arthritis Foundation, and Taiwan GSSA fellowship. References: 1. Yusuf Arthritis Res Ther Louer Arthritis Rheum Knott Osteoarthr Cartilage Glasson Osteoarthr Cartilage Hirabara J Cell Phys Wann Arthritis Res Ther Ohashi J Biol Chem Otranto Wound Rep Regen Cardoso Wound Rep Regen Tang Diabetes Rai Arthritis Rheum Kruger Prog Lipid Res Zhang J Orthop Res Felson Arthritis Rheum 2007 ORS 2014 Annual Meeting Poster No: 0044

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