Mechanisms of action of native collagen type II and Aflapin® on the pathophysiology of osteoarthritis and their evidences

Rakesh Verma; Rohit Nath; Rajesh K. Dhadiwal; Gautam V. Daftary; Mital A. Jolapara; Raj A. Shah; Nikita N. Patil

doi:10.18203/issn.2455-4510.IntJResOrthop20241946

Authors

Rakesh Verma Department of Orthopaedics, JLN Medical College, Ajmer, Rajasthan, India
Rohit Nath Department of Orthopaedics, GSVM Medical College, Kanpur, Uttar Pradesh, India
Rajesh K. Dhadiwal Director, Dhadiwal Hospital, Trimbak Road, Nashik, Maharashtra, India
Gautam V. Daftary Department of Research and Development, Aksigen Hospital Care, Mumbai, Maharashtra, India
Mital A. Jolapara Marketing Department, Aksigen Hospital Care, Mumbai, Maharashtra, India
Raj A. Shah Marketing Department, Aksigen Hospital Care, Mumbai, Maharashtra, India
Nikita N. Patil Department of Medical Services, SIRO Clinpharm Pvt. Ltd., Thane, Maharashtra, India

DOI:

https://doi.org/10.18203/issn.2455-4510.IntJResOrthop20241946

Keywords:

Undenatured collagen, Boswellia serrata extract, Oral tolerance, Cartilage regeneration

Abstract

Osteoarthritis (OA) is a degenerative and chronic inflammatory disease that affects the entire joint tissue such as articular cartilage, synovial membrane, subchondral bone, and ligaments. Imbalance between anabolism and catabolism lead to degradation of articular cartilage which may further initiate inflammatory cascades. There is an interplay of mechanical and immune-mediated injuries that lead to cartilage destruction and inflammation in OA. The mainstay of OA treatment involves drugs like paracetamol and non-steroidal anti-inflammatory drugs (NSAIDs) which provide symptomatic relief in many cases; but are unable to inhibit disease progression. Also, long-term use of these drugs, is associated with major safety concerns. Native collagen type II (NC-II) and Aflapin, especially when used in combination, can slow down the disease progression in OA and serve as a safer and effective treatment option for OA. NC-II is non-hydrolyzed collagen having intact triple helix structure with active epitopes and antigenicity. Aflapin is a novel synergistic composition of Boswellia serrata gum resin having higher composition of 3-O-acetyl-11-keto-betaboswellic acid (AKBA). Various experimental studies have demonstrated the mechanisms by which both these agents exert their benefit in OA. Further, multiple clinical studies have demonstrated the efficacy and safety of NC-II and Aflapin, when used individually or as a combination. This is a narrative review of the pathophysiology of OA, current treatment modalities, and non-clinical and clinical evidence of the beneficial effects of NC-II and Aflapin in the management of OA.

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References

Yuan G, Masuko‐Hongo K, Kato T, Nishioka K. Immunologic intervention in the pathogenesis of

osteoarthritis. Arthritis Rheumatism. 2003;48(3):602-11.

Stabile M, Samarelli R, Trerotoli P, Fracassi L, Lacitignola L, Crovace A, et al. Evaluation of the effects of undenatured type II collagen (UC-II) as compared to robenacoxib on the mobility impairment induced by osteoarthritis in dogs. Veterinary Sci. 2019;6(3):72.

Narayanan G, Gandhi R. Understanding Collagen Supplements in Arthritis-Immunomodulation with Undenatured Collagen II versus Cartilage Building with Hydrolyzed Collagen II. Arch Orthop Rheumatol. 2019;2(2):04-11.

Sun L, Wang X, Kaplan D. A 3D cartilage–inflammatory cell culture system for the modeling of human osteoarthritis. Biomaterials. 2011;32(24):5581-9.

Suva M, Kheni D, Sureja V. Aflapin®: A novel and selective 5-lipoxygenase inhibitor for arthritis management. Indian J Pain. 2018;32(1):16-23.

Hu Q, Ecker M. Overview of MMP-13 as a promising target for the treatment of osteoarthritis. Int J Mol Sci. 2021;22(4):1742.

Prabhoo R, Billa G. Undenatured collagen type II for the treatment of osteoarthritis: a review. Int J Res Orthop. 2018;4(5):684-9.

Honvo G, Lengelé L, Charles A, Reginster J, Bruyère O. Role of collagen derivatives in osteoarthritis and cartilage repair: a systematic scoping review with evidence mapping. Rheumatol Ther. 2020;7:703-40.

Zapata A, Fernández-Parra R. Management of Osteoarthritis and Joint Support Using Feed Supplements: A Scoping Review of Undenatured Type II Collagen and Boswellia serrata. Animals. 2023;13(5):870.

Fernandes T, Gomoll A, Lattermann C, Hernandez A, Bueno D, Amano M. Macrophage: a potential target on cartilage regeneration. Front Immunol. 2020;11:111.

Mahajan R, Rathod N, Narayanan V. Multimodal Anti-Inflammatory Approach to Osteoarthritis Management-Review of T Cell Immunomodulation with Undenatured (Native) Collagen Type II, and LOX Inhibition with Boswellia. Nov Tech Arthritis Bone Res. 2019;3:555618.

Crowley D, Lau F, Sharma P, Evans M, Guthrie N, Bagchi M, et al. Safety and efficacy of undenatured type II collagen in the treatment of osteoarthritis of the knee: a clinical trial. Int J Med Sci. 2009;6(6):312.

Sengupta K, Krishnaraju A, Vishal A, Mishra A, Trimurtulu G, Sarma K, et al. Comparative efficacy and tolerability of 5-Loxin® and Aflapin® against osteoarthritis of the knee: a double blind, randomized, placebo controlled clinical study. Int J Med Sci. 2010;7(6):366.

Gencoglu H, Orhan C, Sahin E, Sahin K. Undenatured type II collagen (UC-II) in joint health and disease: a review on the current knowledge of companion animals. Animals. 2020;10(4):697.

Yatish R, Naveenkumar L, Bilagi A, Joshi D. Evaluation of clinical efficacy of undenatured type ii collagen in the treatment of osteoarthritis of knee. A randomized controlled study. Int J Orthop. 2020;6(2):497-500.

Bagchi D, Misner B, Bagchi M, Kothari S, Downs B, Fafard R, et al. Effects of orally administered undenatured type II collagen against arthritic inflammatory diseases: a mechanistic exploration. Int J Clin Pharmacol Res. 2002;22(3-4):101-10.

Tong T, Zhao W, Wu Y, Chang Y, Wang Q, Zhang L, et al. Chicken type II collagen induced immune balance of main subtype of helper T cells in mesenteric lymph node lymphocytes in rats with collagen-induced arthritis. Inflammation Res. 2010;59:369-77.

Furuzawa‐Carballeda J, Muñoz‐Chable O, Macías‐Hernández S, Agualimpia‐Janning A. Effect of polymerized‐type I collagen in knee osteoarthritis. II. In vivo study. Eur J Clin Invest. 2009;39(7):598-606.

Asnagli H, Martire D, Belmonte N, Quentin J, Bastian H, Boucard-Jourdin M, et al. Type 1 regulatory T cells specific for collagen type II as an efficient cell-based therapy in arthritis. Arthritis Res Ther. 2014;16:1-2.

Müller R, John T, Kohl B, Feldner A, Zreiqat H, Ertel W, et al. Cartilage-specific matrix and integrin expression in three-dimensional articular chondrocyte cultures overexpressing human interleukin-10. Clin Med Arthritis Musculoskelet Disord. 2008;1:CMAMD-S560.

Dai M, Sui B, Xue Y, Liu X, Sun J. Cartilage repair in degenerative osteoarthritis mediated by squid type II collagen via immunomodulating activation of M2 macrophages, inhibiting apoptosis and hypertrophy of chondrocytes. Biomaterials. 2018;180:91-103.

Xu D, Shen W. Chicken collagen type II reduces articular cartilage destruction in a model of osteoarthritis in rats. West Indian Medical J. 2007;56(3):202.

Ammon H, Mack T, Singh G, Safayhi H. Inhibition of leukotriene B4 formation in rat peritoneal neutrophils by an ethanolic extract of the gum resin exudate of Boswellia serrata. Planta Medica. 1991;57(03):203-7.

Safayhi H, Sailer E, Ammon H. Mechanism of 5-lipoxygenase inhibition by acetyl-11-keto-beta-boswellic acid. Mol Pharmacol. 1995;47(6):1212-6.

Siemoneit U, Pergola C, Jazzar B, Northoff H, Skarke C, Jauch J, et al. On the interference of boswellic acids with 5-lipoxygenase: Mechanistic studies in vitro and pharmacological relevance. Eur J Pharmacol. 2009;606(1-3):246-54.

Chevrier M, Ryan A, Lee D, Zhongze M, Wu-Yan Z, Via C. Boswellia carterii extract inhibits TH1 cytokines and promotes TH2 cytokines in vitro. Clin Vaccine Immunol. 2005;12(5):575-80.

Gayathri B, Manjula N, Vinaykumar K, Lakshmi B, Balakrishnan A. Pure compound from Boswellia serrata extract exhibits anti-inflammatory property in human PBMCs and mouse macrophages through inhibition of TNFα, IL-1β, NO and MAP kinases. Int immunopharmacol. 2007;7(4):473-82.

Sengupta K, Kolla J, Krishnaraju A, Yalamanchili N, Rao C, Golakoti T, et al. Cellular and molecular mechanisms of anti-inflammatory effect of Aflapin: a novel Boswellia serrata extract. Mol Cellular Biochem. 201;354:189-97.

Syrovets T, Büchele B, Krauss C, Laumonnier Y, Simmet T. Acetyl-boswellic acids inhibit lipopolysaccharide-mediated TNF-α induction in monocytes by direct interaction with IκB kinases. J Immunol. 2005;174(1):498-506.

Kumar R, Singh S, Saksena A, Pal R, Jaiswal R, Kumar R. Effect of Boswellia serrata extract on acute inflammatory parameters and tumor necrosis factor-α in complete Freund's adjuvant-induced animal model of rheumatoid arthritis. Int J Appl Basic Med Res. 2019;9(2):100-6.

Umar S, Umar K, Sarwar A, Khan A, Ahmad N, Ahmad S, et al. Boswellia serrata extract attenuates inflammatory mediators and oxidative stress in collagen induced arthritis. Phytomedicine. 2014;21(6):847-56.

Azeem MA, Patil R. The study of undenatured type II collagen in the knee osteoarthritis. Int J Orthop. 2019;5(01):172-5.

Mehra A, Anand P, Borate M, Paul P, Kamble S, Mehta K, et al. A non-interventional, prospective, multicentric real life Indian study to assess safety and effectiveness of un-denatured type 2 collagen in management of osteoarthritis. Int J Res Orthop. 2019;5(2):315.

Lugo J, Saiyed Z, Lau F, Molina J, Pakdaman M, Shamie A, et al. Undenatured type II collagen (UC-II®) for joint support: a randomized, double-blind, placebo-controlled study in healthy volunteers. J Int Soc Sports Nutr. 2013;10(1):48.

Bakilan F, Armagan O, Ozgen M, Tascioglu F, Bolluk O, Alatas O. Effects of native type II collagen treatment on knee osteoarthritis: a randomized controlled trial. Eurasian J Med. 2016;48(2):95.

Lugo J, Saiyed Z, Lane N. Efficacy and tolerability of an undenatured type II collagen supplement in modulating knee osteoarthritis symptoms: a multicenter randomized, double-blind, placebo-controlled study. Nutr J. 2015;15:1-5.

Sadigursky D, Magnavita V, Sá C, Monteiro H, Braghiroli O, Matos M. Undenatured collagen type II for the treatment of osteoarthritis of the knee. Acta Ortop Bras. 2022;30:e240572.

Vishal A, Mishra A, Raychaudhuri S. A double blind, randomized, placebo controlled clinical study evaluates the early efficacy of Aflapin® in subjects with osteoarthritis of knee. Int J Med Sci. 2011;8(7):615.

Karlapudi V, Sunkara K, Konda P, Sarma K, Rokkam M. Efficacy and safety of Aflapin®, a novel Boswellia serrata extract, in the treatment of osteoarthritis of the knee: A short-term 30-day randomized, double-blind, placebo-controlled clinical study. JANA. 2023;42(2):159-68.

Kimmatkar N, Thawani V, Hingorani L, Khiyani R. Efficacy and tolerability of Boswellia serrata extract in treatment of osteoarthritis of knee-a randomized double blind placebo controlled trial. Phytomedicine. 2003;10(1):3-7.

Sengupta K, Alluri K, Satish A, Mishra S, Golakoti T, Sarma K, et al. A double blind, randomized, placebo controlled study of the efficacy and safety of 5-Loxin® for treatment of osteoarthritis of the knee. Arthritis Res Ther. 2008;10:1-1.

Jain A, Jain K, Vijayaraghavan N. AflaB2® and osteoarthritis: a multicentric, observational, post-marketing surveillance study in Indian patients suffering from knee osteoarthritis. Int J Res Orthop. 2020;7:110.