Skip to main content

Astaxanthin ameliorates cartilage damage in experimental osteoarthritis. Huang and Chen.

By February 27, 2015March 9th, 2015Science

By Timothy J. King, Ph.D., Vice President, Research

Osteoarthritis Background

Osteoarthritis (OA) is the most common form of arthritis, a chronic disease of aging.  Effective and safe long-term treatment for most OA patients is not available, creating a large unmet medical need. The potential market for OA is very large, where it is estimated that more than 150 million middle class people globally suffer from OA.  Symptomatic knee OA alone affects roughly 12% of persons 60 years or older.  The number of people with arthritis is projected to grow substantially, with the CDC estimating that by 2030 more than 67 million people in the U.S. alone will have doctor diagnosed arthritis ( – most of whom will have OA. Assuming $1/day for treatment, the potential market could exceed $50 billion annually.

While OA has been viewed historically as a disease of increased biomechanical stress due to increased loadbearing (obesity), recent scientific progress points towards chronic inflammation as contributing to and driving OA disease progression.  In particular, as many otherwise healthy, younger patients developed OA decades after acute sports-related injuries, it became evident that more than simple loadbearing mechanisms contribute to disease pathobiology.  Additionally, the importance of obesity-related mechanisms, including altered expression of fat-associated inflammatory and metabolic regulatory mediators, suggest that even the influence of obesity on OA disease pathology is more complicated than simple mechano-pathology.  Obesity’s impact on OA pathology is likely to grow as projections by the CDC suggest if current trends continue, by 2030, 20% of US population will be over the age of 65 with 86% of the population being obese.

Current treatments for OA include anti-inflammatories such as corticosteroids; non-steroidal anti-inflammatories (NSAIDS) including Celebrex, ibuprofen, and Naproxen; pain relievers including acetaminophen (paracetamol) and opioids (Tramadol); and glucosamine/chondroitin. The anti-inflammatory drugs act via inhibition of critical intracellular pathways and mediators including TNF-α, COX1/2, NF-κB, prostaglandins, etc. In addition, restoration of articular cartilage by supplementation with the ECM components chondroitin sulfate and glucosamine constitute a significant strategy for amelioration of OA symptoms. While short-term partial relief is achieved with steroidal treatments, diminished long-term benefits and significant adverse events prevent sustained dosing. Likewise, currently available NSAIDS offer anti-inflammatory action but exhibit unacceptable long-term adverse events including risks of bleeding or cardiovascular events. Pain relievers such as acetaminophen have risks of hepatotoxicity and opioids, of course, are not suitable for chronic administration.  While smaller human studies with glucosamine and chondroitin sulfate suggest modest OA efficacy, larger studies demonstrated no benefit. Ultimately, effective treatment of OA requires a safer, multi-faceted anti-inflammatory molecule able to affect a multitude of OA-related pathomechanisms with minimal adverse effects when used over long time periods. We believe astaxanthin (ASTX) is that molecule.

Astaxanthin (ASTX) Background

ASTX is a safe, orally bioavailable, naturally occurring molecule with strong antioxidant and anti-inflammatory activity [1]. Following oral administration and intestinal uptake, ASTX is delivered initially to the liver via chylomicrons and subsequently distributed to tissues throughout the body via plasma lipoprotein particles including VLDL, HDL and LDL. Once in the cell, ASTX accumulates within various organelles including plasma, nuclear, endoplasmic reticular and mitochondrial membranes. Localization within mitochondria is highly restricted by the cell and allows ASTX to uniquely regulate oxidative and nitrosative stress in a privileged location critical to normal metabolic function and often at the heart of cell death, metabolic dysfunction and aging. Due to its chemical structure, ASTX completely traverses the lipid bilayer component of cell membranes, facilitating its biphasic (aqueous and lipid) anti-oxidant functions. In addition to mitochondrial influence, ASTX’s remarkable anti-oxidant functions have the capacity to influence intracellular inflammation and metabolic pathway signaling as many of these pathways are directly modulated by inflammatory and oxidative stress mediators.

ASTX has been shown in humans to significantly lower important inflammatory and metabolic disease measures including tumor necrosis factor-alpha (TNF-a), low density lipoprotein cholesterol (LDL-C), apolipoprotein B (ApoB) and triglycerides while significantly raising adiponectin and high density lipoprotein cholesterol (HDL-C) levels [2-4]. ASTX has also positively affected markers of oxidative stress in humans including; significantly lowering isoprostanes and malondialdehyde (MDA) levels and significantly increasing total antioxidant capacity (TAC) and superoxide dismutase (SOD)[4,5]. ASTX, and ASTX delivered via related Cardax proprietary conjugates, have demonstrated efficacy in models of inflammatory-mediated disease including reduction of TNF-a levels equivalent to a steroid, reduction of cholesterol levels, reduction of elevated triglycerides, decrease in atheroma formation, and reduction in blood clot formation [6-10]. Additionally, many studies support the strong influence of ASTX on mitochondrial functionality as well as inflammatory and metabolic intracellular signaling in animal and cell-based models [1,11-14].

A multitude of published ASTX studies suggest it will be effective in the treatment of OA. As an overview [15], OA pathology includes increased joint loading (or acute injury), accelerated breakdown of articular extracellular matrix (catabolism of ECM), decreased cartilage cell (chondrocyte) production of articular ECM products (anabolism of ECM), increased inflammatory cytokine levels (TNF-α, IL-1β, IL-6, PGE-2, NO, etc.), altered cartilage cell differentiation/behavior (chondrocyte hypertrophy) and increased chondrocytic cell death. As OA progresses, inflammatory mediators influence chondrocytes to produce more ECM digesting proteolytic enzymes (MMP-13 in particular) and decrease expression of joint-stabilizing proteoglycan ECM products (aggrecans, collagen type 2). Chondrocytes begin to stop normal collagen type 2 production and switch to expression of non-joint collagen types (collagens type 1 and 10). These physiological changes result in a stiffer joint with diminished capacity to cushion mechanical stress. Ultimately, as the joint matrix is degraded and altered, chondrocytes die (apoptosis) resulting in a non-supportive joint tissue with little chance of restoration due to the pathological absence of contributing cell types (chondrocytes).

In detail, increased levels of the inflammatory mediator IL-1β stimulates chondrocytes to increase MMP-13 levels, via upregulation of the NF-κB pathway, while increased levels of TNF-α suppress production of proteoglycan/collagen ECM products by inhibiting the PI3K/AKT pathway. Additionally, loss of adiponectin levels (inversely correlated with obesity and TNF-α) leads to decreased levels of TIMP-2, an inhibitor of MMP-13 and increased ECM degradation.  Meanwhile, increased mitochondrial dysfunction leads to production of excess reactive oxygen and nitrogen species, induction of JNK signaling pathways and ultimately chondrocytic death induction (apoptosis). Importantly, inflammatory mediators converge on NF-κB pathways that induce production of numerous other inflammatory mediators that ultimately contribute to accelerate OA progression including PGE-2, iNOS, IL-6, etc.

Toward ameliorating OA pathophysiology, ASTX has been shown to, at very low doses, reduce TNF-a in humans [2].  In rodents, ASTX reduces TNF-a equivalent to a corticosteroid, the gold standard of anti-inflammatory compounds, with no evidence of immunosuppressive effects [6]. ASTX also significantly decreases other important mediators of inflammation in animal models including CRP, IL-1β, PGE-2, IL-6, NF-κB, iNOS, and nitric oxide (NO)[6,7,13,14]. The ability of ASTX to decrease inflammatory mediators will result in decreased matrix breakdown via diminished MMP protease action [16,17]. In addition, ASTX will increase matrix production by upregulation of adiponectin levels, as supported by data from human and animal studies, thereby increasing expression of the MMP inhibitor, TIMP-2 [2,3,18]. In animal models, ASTX has also been shown to increase activation of the PI3K/AKT signaling pathway, often dysregulated and inhibited by oxidative stress and inflammation, which will lead to increased proteoglycan production and restoration of mechanical support to the joint [13,19]. ASTX localizes to mitochondria and has been shown to decrease oxidative stress, stabilize mitochondrial membranes leading to decreased pro-apoptotic mediators (Bax, cytochrome C release) and increased anti-apoptotic mediators (Bcl-2), and to decrease subsequent activation of JNK pathways that induce cell death [12, 19-21]. Stabilization of mitochondria and inhibition of apoptotic pathways will prolong chondrocytic cell life and contribute to joint matrix component maintenance. Likewise, ASTX has been shown in animals to upregulate PGC-1α, a master regulator of mitochondrial biogenesis, as well as critical metabolic regulators such as CPT-1 [22, 23]. All this scientific evidence, in both humans and animal models, highlight the capacity of ASTX to affect important mechanisms critical to osteoarthritis pathology in humans (oxidative stress, inflammation) and underscores the enormous potential of ASTX to ameliorate disease progression and symptoms in OA patients.

Featured Recent Article

To add important in vivo ASTX efficacy to previously published cell-based studies supporting ASTX effects on OA, Huang and Chen have recently published a study evaluating the capacity of synthetic ASTX to ameliorate OA disease pathology using a commonly employed OA model wherein rabbits undergo knee joint anterior cruciate ligament transection (ACLT). ACLT transection causes joint instability ultimately leading to cartilage destruction and OA-like pathology. Specifically, 2.0-2.5 kg New Zealand rabbits received: 1) an intra-articular injection of synthetic ASTX (Sigma-Aldrich source, 0.3ml of 50uM solution, N=8) once weekly for 6 weeks starting on the day of the operation, or 2) a vehicle-only injection (DMSO, N=8) once weekly for 6 weeks starting on the day of operation, or 3) a sham operation (N=8, ACLT exposed without transection). Knees were evaluated using histological and morphological criteria as well as gene expression profiling of the cartilage-degrading enzymes MMP-1, 3 and 13.

Importantly, they found that ASTX treatment diminished cartilage reduction in vivo. Histologically, ASTX significantly decreased cartilage degradation as quantified using the Mankin scoring system established for stained articular cartilage (p<0.05). Additionally, ASTX diminished lesion severity based on cartilage morphology, albeit not statistically significantly. These histological/morphological results strongly support the potential of ASTX for amelioration of OA related joint degradation in clinical applications. Furthermore, gene expression analysis of cartilage revealed a strong and significant effect of ASTX toward decreasing expression levels of the cartilage degrading enzymes MMPs (MMP-1, 3, 13) compared to the vehicle-treated group. In summary, here is the first example of an in vivo study supporting the capacity of ASTX to reduce OA pathology and underscores the potential clinical applicability of ASTX in OA patients. Reduction of MMP expression by ASTX treatment underscores one possible mechanism of action by which ASTX can act to protect cartilage destruction in vivo as supported by aforementioned in vitro cell studies [16,17,24].


Featured Reference

Huang, L.-J. and Chen W.-P., Modern Rheumatology January 21:1-19, 2015.

Additional References

  1. Ambati, R.R. et al., Marine Drugs 12:128-152, 2014.
  2. Uchiyama, A. and Okada, Y., Clin. Biochem. Nutr. 43 Suppl (1);38-43, 2008.
  3. Yoshida, H. et al., Atherosclerosis 209(2):520-523, 2010.
  4. Choi, H.D. et al., Plant Foods Hum. Nutr. 66(4):363-369, 2011.
  5. Choi, H.D. et al., Phytotherapy Res. 25(12):1813-1818, 2011.
  6. Ohgami, K. et al., Ophth. Vis. Sci. 44(6):2694-2701, 2003.
  7. Suzuki, Y. et al., Eye Res. 82:275-281, 2006.
  8. Bhuvaneswari, S. et al., Process Biochem. 45:1406-1414, 2010.
  9. Ryu, S.K. et al., Atherosclerosis 222(1):99-105, 2012.
  10. Khan, S.K. et al., Res. 126:299-305, 2010.
  11. Park, J.S. et al., Anim. Sci. 91:268-275, 2013.
  12. Wolf, A.M. et al., Nutr. Biochem. 21(5):381-389, 2010.
  13. Arunkumar, E. et al., Food & Function 3(2):120-126, 2011.
  14. Chan, K.-C. et al., Food Sci. 77(2)H76-H80, 2012.
  15. Maldonado, M. and Nam, Biomed. Res. Int. (284873 ID), 2013.
  16. Kishimoto, Y. et al., J. Nutr. 49(2):119-126, 2009.
  17. Chen, W.-P. et al., Immunopharm. 19(1):174-177, 2014.
  18. Hussein, G. et al., Life Sci. 80:522-529, 2007.
  19. Bhuvaneswari, S. et al., J. Physiol. Pharmacol. 90:1544-1552, 2012.
  20. Lee, D.-H. et al., Food Chem. Toxicol. 49(1):271-280, 2011.
  21. Liu, X. et al., Brain Res. 1254:18-27, 2009.
  22. Liu, P.-H. et al., Clin. Biochem. Nutr. 54(2):86-89, 2014.
  23. Aoi, W. et al., Biophys. Res. Comm. 366:892-897 2008.
  24. Kimble, L.L. et al., J. Adv. Food Sci. Tech. 2:37-51, 2013.