Oral Absorbation of Hyaluronic Acid

SCIENCE SUPPORTING ORAL HYALURONIC ACID

Hyaluronic Acid – General

• Synovial fluid has the highest concentration of hyaluronic acid (HA) anywhere in the body (3-4 mg/ml) – Balazs et al[1]

• The viscosity of synovial fluid is attributed to HA resulting in a coefficient of friction of nearly zero in joint cartilage – Seror et al[2]
• Patients with osteoarthritis have diminished concentrations of HA in their synovial fluid
• The functions of HA in the joints includes

◊ Protecting the outer layer of cartilage – Ghosh et al[3] , Schiavinato et al[4]

◊ Blocking synovial inflammation – Frizziero et al[5] , Pasquali et al[6]

◊ Increasing chondrocyte density – Guidolin et al[7]

◊ Promoting synovium metabolism – Maniwa et al[8]

◊ Normalizing synovial fluid – Asari et al[9]

◊ Treating sharp pain – Day et al[10]

Therefore, there is extensive scientific support confirming HA has a strong relationship with knee joint health.

Oral Absorption Of Hyaluronic Acid

• Study examining the absorption, distribution and excretion of 99m technetium labeled HA (1,000,000 MW) after a single oral administration in Wistar rats and Beagle dogs – Balogh et al[11]

◊ 13.3% of the oral dose was absorbed and taken up in joints and connective tissue

◊ Scintigraphy scan of the dog chest showing distribution of hyaluronic acid in the joints, bones and salivary glands two hours after administration

◊ Scintigraphic scan of rat chest showing distribution in joints, bones, muscles and salivary glands 4 hours after administration

Mechanism Of Oral Hyaluronic Acid Treatment for Knee Pain

• By decreasing the levels of inflammatory substances such as PGE2 HA reduces pain – Santangelo et al [12] , Ikeda et al [13]
• Oral HA binds to an intestinal receptor (TLR-4), this results in anti-inflammation in arthritis by:

◊ Enhancing the production of the IL-10 an anti-inflammatory cytokine

◊ Up regulates suppressor of SOCS3 cytokine expression and down regulates an inflammatory cytokine pleiotrophin

• These results indicate that HA absorption in the intestine contributes to reduced inflammation in arthritis – Asari et al[14]
• An analysis of serum and synovial fluid in a controlled clinical study illustrates that:

◊ Inflammatory cytokine levels were significantly increased in the placebo group (p<0.05) and significantly reduced in the HA group (P<0.05)

◊ Bradykinin, which relates to inflammation and pain, and leptin, which is related to osteoarthritis caused by obesity, the levels of both substances were significantly lower in the HA group than the placebo group (P<0.05)

• This study demonstrates that the oral intake of HA is beneficial in treating osteoarthritis – Nelson et al[15]

Use Of Oral Hyaluronic Acid In Horses

• “Serum Hyaluronic Acid levels in Horses after Oral and Intravenous Administration” – Pierce DVM

10 horses divided into 3 groups

◊ Baseline blood samples taken at the beginning of the study

◊ Daily blood samples taken for 7 days

◊ Results

◦ Oral group

- Oral HA group had the highest level of serum HA

- Oral HA group was the only group to have a substantial increase in serum HA on day 7

◦ Intravenous group

- had a slight elevation in HA on day 4

◦ Control group

- had constant levels for 7 days

• A controlled study provides objective evidence that oral HA reduces joint effusion post operatively following arthroscopic surgery – Bergin et alBergin et al[16]

◊ 48 yearlings divided into 2 groups, 100 mg of HA daily and control

◊ HA significantly reduced joint swelling compared to no treatment

• Data from a study using orally administered HA was presented at a 2003 meeting of the Matrix Biology Institute

◊ 100 mg of hyaluronic acid administered orally daily

◊ There was a reduced number of times veterinarians were asked to examine racing thoroughbreds for lameness

LITERATURE CITED

[1] Balazs EA, Watson D, Duff IF, Roseman S. Hyaluronic acid in synovial fluid. I. Molecular parameters of hyaluronic acid in normal and arthritic human fluids. Arthritis Rheum. 1967;10:357-76. doi: 10.1002/art.1780100407.

[2] Seror J, Merkher Y, Kampf N, Collinson L, Day AJ, Maroudas A, et al. Articular cartilage proteoglycans as boundary lubricants: structure and frictional interaction of surface-attached hyaluronan and hyaluronan--aggrecan complexes. Biomacromolecules. 2011;12:3432-43. doi: 10.1021/bm2004912.

[3] Ghosh P, Holbert C, Read R, Armstrong S. Hyaluronic acid (hyaluronan) in experimental osteoarthritis. J Rheumatol Suppl. 1995;43:155-7.

[4] Schiavinato A, Lini E, Guidolin D, Pezzoli G, Botti P, Martelli M, et al. Intraarticular sodium hyaluronate injections in the Pond-Nuki experimental model of osteoarthritis in dogs. II. Morphological findings. Clin Orthop Relat Res. 1989;241:286-99.

[5] Frizziero L, Govoni E, Bacchini P. Intra-articular hyaluronic acid in the treatment of osteoarthritis of the knee: clinical and morphological study. Clin ExpRheumatol. 1998;16:441-9.

[6] Pasquali Ronchetti I, Guerra D, Taparelli F, Boraldi F, Bergamini G, Mori G, et al. Morphological analysis of knee synovial membrane biopsies from a randomized controlled clinical study comparing the effects of sodium hyaluronate (Hyalgan) and methylprednisolone acetate (Depomedrol) in osteoarthritis. Rheumatology. 2001;40:158-69. doi: 10.1093/rheumatology/40.2.158.

[7] Guidolin DD, Ronchetti IP, Lini E, Guerra D, Frizziero L. Morphological analysis of articular cartilage biopsies from a randomized, clinical study comparing the effects of 500-730 kDa sodium hyaluronate (Hyalgan) and methylprednisolone acetate on primary osteoarthritis of the knee. Osteoarthritis Cartilage. 2001;9:371-81. doi: 10.1053/joca.2000.0398.

[8] Maniwa S, Ochi M, Motomura T, Nishikori T, Chen J, Naora H. Effects of hyaluronic acid and basic fibroblast growth factor on motility of chondrocytes and synovial cells in culture. Acta Orthop Scand, 2001;72:299-303. doi: 10.1080/00016470152846664.

[9] Asari A, Miyauchi S, Matsuzaka S, Ito T, Kominami E, Uchiyama Y. Molecular eight-dependent effects of hyaluronate on the arthritic synovium. Arch Histol Cytol. 1998;61:125-35. doi: 10.1679/aohc.61.125.

[10] Day R, Brooks P, Conaghan PG, Petersen M. A double blind, randomized, multicenter, parallel group study of the effectiveness and tolerance of intraarticular hyaluronan in osteoarthritis of the knee. J Rheumatol. 2004;31:775-82.

[11] Balogh L, Polyak A, Mathe D, Kiraly R, Thuroczy J, Terez M, et al. Absorption, uptake and tissue affinity of high-molecular-weight hyaluronan after oral administration in rats and dogs. J Agric Food Chem. 2008;56:10582-93. doi: 10.1021/jf8017029.

[12] Santangelo KS, Johnson AL, Ruppert AS, Bertone AL. Effects of hyaluronan treatment on lipopolysaccharide-challenged fibroblast-like synovial cells. Arthritis Res Ther. 2007;9:R1. doi: 10.1186/ar2104.

[13] Ikeda K. Changes in synovial fluid markers and clinical effects after intra-articular injection of sodium hyaluronate with particular reference to the anti-inflammatory effect in terms of prostaglandin E₂ concentration. Tokyo Women’s Medical University. 1998;68:22-36.

[14] Asari A, Kanemitsu T, Kurihara H. Oral administration of high molecular weight hyaluronan (900 kDa) controls immune system via Toll-like receptor 4 in the intestinal epithelium. J Biol Chem. 2010;285:24751-8. doi: 10.1074/jbc.M110.104950.

[15] Nelson FR, Zvirbulis RA, Zonca B, Li KW, Turner SM, Pasierb M, et al. The effects of an oral preparation containing hyaluronic acid (Oralvisc) on obese knee osteoarthritis patients determined by pain, function, bradykinin, leptin, inflammatory cytokines, and heavy water analyses. Rheumatol Int. 2015;35:43-52. doi: 10.1007/s00296-014-3047-6.

[16]Bergin BJ, Pierce SW, Bramlage LR, Stromberg A. Oral hyaluronan gel reduces post operative tarso crural effusion in the yearling thoroughbred. Equine Vet J. 2006;38(4):375-8