Skip to main content
SpringerLink
Log in

Anti-Inflammatory Effects of Boric Acid in Treating Knee Osteoarthritis: Biochemical and Histopathological Evaluation in Rat Model

  • Research
  • Published:
Biological Trace Element Research Aims and scope Submit manuscript

Abstract

This study aimed to examine the anti-inflammatory properties of boric acid (BA) in treating knee osteoarthritis (KOA) in rats, evaluating its biochemical and histopathological therapeutic effects. A KOA rat model was induced by injecting monosodium iodoacetate into the knee joint. Random assignment was performed for the experimental groups as follows: group-1(control), group-2(KOA control), group-3 (BA:4 mg/kg, orally), group-4(BA:10 mg/kg, orally), group-5(BA:4 mg/kg, intra-articularly), and group-6(BA:10 mg/kg, intra-articularly). The rats received 100 µL of BA intra-articularly on days 1, 7, 14, and 21 or 1 mL orally once a day (5 days/week) for 4 weeks. Serum levels of interleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), and activity of matrix metalloproteinase-13 (MMP-13) were measured. Histopathological and immunohistochemical analyses were performed on knee joint samples using specific antibodies for IL-1β, TNF-α, MMP-13, and nitric oxide synthase-2 (NOS-2). Group-2 exhibited higher serum IL-1β and TNF-α levels and MMP-13 activity than group-1 (P < 0.05). However, IL-1β and TNF-α levels and MMP-13 activity were lower in all treatment groups than in group-2, with statistically significant reductions observed in groups-4, 5, and 6. Histopathologically, group-2 displayed joint space narrowing, cartilage degeneration, and deep fissures. Groups-5 and 6 demonstrated significant joint space enlargement, articular cartilage tissue regeneration, and immunostaining patterns similar to those in group-1. Immunohistochemically, group-2 showed significant increases in IL-1β, TNF-α, MMP-13, and NOS-2 expression. However, all treatment groups exhibited reductions in these expression levels compared to group-2, with statistically significant decreases observed in groups-5 and 6 (P < 0.01). BA shows potential efficacy in reducing inflammation in experimental KOA model in rats. It may be a promising therapeutic agent for KOA, warranting further clinical studies for validation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data Availability

All data are presented in the manuscript.

Abbreviations

BA, H3BO3 :

Boric acid

CRP:

C-reactive protein

IHC:

Immunohistochemistry

IL-1β:

Interleukin-1β

IRS:

Immunoreactive score

i.a.:

Intraarticular

iNOS:

Inducible NO synthase

KOA:

Knee osteoarthritis

MMP-13:

Matrix metalloproteinase-13

MIA:

Monosodium iodoacetate

NOS-2:

Nitric oxide synthase-2

OA:

Osteoarthritis

po:

Orally

ROS:

Reactive oxygen species

TNF-α:

Tumor necrosis factor-α

References

  1. Krasselt M, Baerwald C (2022) Osteoarthritis: what’s new? Deutsche Medizinische Wochenschrift (1946) 147(6):344–348

    PubMed  Google Scholar 

  2. Cui A et al (2020) Global, regional prevalence, incidence and risk factors of knee osteoarthritis in population-based studies. EClinMed 29–30:100587

  3. Samara O et al (2022) Ultrasound-guided intra-articular injection of expanded umbilical cord mesenchymal stem cells in knee osteoarthritis: a safety/efficacy study with MRI data. Regen Med 17(5):299–312

    Article  CAS  PubMed  Google Scholar 

  4. Pulsatelli L et al (2013) New findings in osteoarthritis pathogenesis: therapeutic implications. Ther Adv Chron Dis 4(1):23–43

    Article  CAS  Google Scholar 

  5. Scanzello CR, Goldring SR (2012) The role of synovitis in osteoarthritis pathogenesis. Bone 51(2):249–257

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Wang T, He C (2018) Pro-inflammatory cytokines: the link between obesity and osteoarthritis. Cytokine Growth Factor Rev 44:38–50

    Article  PubMed  Google Scholar 

  7. Kapoor M et al (2011) Role of proinflammatory cytokines in the pathophysiology of osteoarthritis. Nat Rev Rheumatol 7(1):33–42

    Article  CAS  PubMed  Google Scholar 

  8. Ioan-Facsinay A, Kloppenburg M (2013) An emerging player in knee osteoarthritis: the infrapatellar fat pad. Arthritis Res Ther 15(6):1–9

    Article  Google Scholar 

  9. Scanzello CR, Loeser RF (2015) Editorial: inflammatory activity in symptomatic knee osteoarthritis: not all inflammation is local. Arthritis Rheumatol 67(11):2797–2800

    Article  PubMed  PubMed Central  Google Scholar 

  10. Smith RA, McBroom RB (2000) Boron oxides, boric acid, and borates. Kirk‐Othmer Encycl Chem Technol 4:241–294

    Google Scholar 

  11. Yıldız k et al (2022) Therapeutic effects of boric acid in a septic arthritis model induced by Escherichia coli in Rats. Biol Trace Element Res 200:4762–4770

    Article  Google Scholar 

  12. Baygar T et al (2022) In vitro biological activities of potassium metaborate; antioxidative, antimicrobial and antibiofilm properties. J Boron 7(2):475–481

    Google Scholar 

  13. Soriano-Ursúa MA, Farfán-García ED, Geninatti-Crich S (2019) Turning fear of boron toxicity into boron-containing drug design. Curr Med Chem 26(26):5005–5018

    Article  PubMed  Google Scholar 

  14. Pizzorno L (2015) Nothing boring about boron. Integr Med: Clinician’s J 14(4):35

    Google Scholar 

  15. Zheng K et al (2020) Incorporation of boron in mesoporous bioactive glass nanoparticles reduces inflammatory response and delays osteogenic differentiation. Part Part Syst Charact 37(7):2000054

    Article  CAS  Google Scholar 

  16. Ince S et al (2019) Boron ameliorates arsenic-induced DNA damage, proinflammatory cytokine gene expressions, oxidant/antioxidant status, and biochemical parameters in rats. J Biochem Mol Toxicol 33(2):e22252

    Article  PubMed  Google Scholar 

  17. Nielsen FH (2014) Update on human health effects of boron. J Trace Elem Med Biol 28(4):383–387

    Article  CAS  PubMed  Google Scholar 

  18. Yamada EF et al (2020) Photobiomodulation therapy in knee osteoarthritis reduces oxidative stress and inflammatory cytokines in rats. J Biophotonics 13(1):e201900204

    Article  CAS  PubMed  Google Scholar 

  19. Kaymaz B et al (2016) Effects of boric acid on the healing of Achilles tendons of rats. Knee Surg Sports Traumatol Arthrosc 24:3738–3744

    Article  PubMed  Google Scholar 

  20. Tekeli H, Asıcı GSE, Bildik A (2021) Anti-inflammatory effect of boric acid on cytokines in ovariectomy-induced rats. Cell Mol Biol (Noisy-le-grand) 67(4):313–320

    Article  Google Scholar 

  21. Korkmaz M et al (2019) Effect of boron on the repair of osteochondral defect and oxidative stress in rats: an experimental study. Biol Trace Elem Res 187:425–433

    Article  CAS  PubMed  Google Scholar 

  22. Demirci T et al (2019) The protective effect of N-acetylcysteine against methotrexate-induced hepatotoxicity in rat. Eurasian J Med Investig 3(3):219–226

    Google Scholar 

  23. Scognamiglio F et al (2020) A hydrogel system based on a lactose-modified chitosan for viscosupplementation in osteoarthritis. Carbohyd Polym 248:116787

    Article  CAS  Google Scholar 

  24. Martin JA, Buckwalter JA (2001) Roles of articular cartilage aging and chondrocyte senescence in the pathogenesis of osteoarthritis. Iowa Orthop J 21:1–7

    CAS  PubMed  PubMed Central  Google Scholar 

  25. Altay MA et al (2015) Evaluation of prolidase activity and oxidative status in patients with knee osteoarthritis: relationships with radiographic severity and clinical parameters. Rheumatol Int 35:1725–1731

    Article  CAS  PubMed  Google Scholar 

  26. Malfait A-M (2016) Osteoarthritis year in review 2015: biology. Osteoarthritis Cartil 24(1):21–26

    Article  CAS  Google Scholar 

  27. Goldring MB, Otero M (2011) Inflammation in osteoarthritis. Curr Opin Rheumatol 23(5):471

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Lee H et al (2014) Effects of deer bone extract on the expression of pro-inflammatory cytokine and cartilage-related genes in monosodium iodoacetate-induced osteoarthritic rats. Biosci Biotechnol Biochem 78(10):1703–1709

    Article  CAS  PubMed  Google Scholar 

  29. Wojdasiewicz P, Poniatowski ŁA, Szukiewicz D (2014) The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediators Inflamm 2014

  30. Massicotte F et al (2002) Can altered production of interleukin-1β, interleukin-6, transforming growth factor-β and prostaglandin E2 by isolated human subchondral osteoblasts identify two subgroups of osteoarthritic patients. Osteoarthritis Cartil 10(6):491–500

    Article  CAS  Google Scholar 

  31. Yunus MHM, Nordin A, Kamal H (2020) Pathophysiological perspective of osteoarthritis. Medicina 56(11):614

    Article  PubMed  PubMed Central  Google Scholar 

  32. Tudorachi NB et al (2021) The implication of reactive oxygen species and antioxidants in knee osteoarthritis. Antioxidants 10(6):985

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Wang M-N et al (2020) Research of inflammatory factors and signaling pathways in knee osteoarthritis. Zhongguo gu Shang= China J Orthop Traumatol 33(4):388–392

  34. Vitale ND et al (2019) Innovative regenerative medicine in the management of knee OA: the role of autologous protein solution. J Clin Orthop Trauma 10(1):49–52

    Article  PubMed  Google Scholar 

  35. Shi GX et al (2020) Effect of electro-acupuncture (EA) and manual acupuncture (MA) on markers of inflammation in knee osteoarthritis. J Pain Res 13:2171–2179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Gundogdu G et al (2020) Investigation of the efficacy of daidzein in experimental knee osteoarthritis-induced with monosodium iodoacetate in rats. Clin Rheumatol 39(8):2399–2408

    Article  PubMed  Google Scholar 

  37. Gorustovich AA et al (2008) A histomorphometric study of alveolar bone modelling and remodelling in mice fed a boron-deficient diet. Arch Oral Biol 53(7):677–682

    Article  CAS  PubMed  Google Scholar 

  38. Sheng MH-C et al (2001) Dietary boron supplementation enhanced the action of estrogen, but not that of parathyroid hormone, to improve trabecular bone quality in ovariectomized rats. Biol Trace Elem Res 82:109–123

    Article  CAS  PubMed  Google Scholar 

  39. Sogut I et al (2015) Effect of boric acid on oxidative stress in rats with fetal alcohol syndrome. Exp Ther Med 9(3):1023–1027

    Article  CAS  PubMed  Google Scholar 

  40. Üstündağ A et al (2014) Protective effect of boric acid on lead-and cadmium-induced genotoxicity in V79 cells. Arch Toxicol 88:1281–1289

    Article  PubMed  Google Scholar 

  41. Devirian TA, Volpe SL (2003) The Physiological Effects of Dietary Boron. Crit Rev Food Sci Nutr 43(2):219–231

    Article  CAS  PubMed  Google Scholar 

  42. Rossol M et al (2012) Extracellular Ca2+ is a danger signal activating the NLRP3 inflammasome through G protein-coupled calcium sensing receptors. Nat Commun 3(1):1329

    Article  PubMed  Google Scholar 

  43. Capati MLF et al (2016) Boron accelerates cultured osteoblastic cell activity through calcium flux. Biol Trace Elem Res 174:300–308

    Article  CAS  PubMed  Google Scholar 

  44. Naghii MR, Torkaman G, Mofid M (2006) Effects of boron and calcium supplementation on mechanical properties of bone in rats. BioFactors 28(3–4):195–201

    Article  CAS  PubMed  Google Scholar 

  45. Scorei ID, Scorei RI (2013) Calcium fructoborate helps control inflammation associated with diminished bone health. Biol Trace Elem Res 155:315–321

    Article  CAS  PubMed  Google Scholar 

  46. Tanaka M, Fujiwara T (2008) Physiological roles and transport mechanisms of boron: perspectives from plants. Pflügers Archiv-Eur J Physiol 456:671–677

    Article  CAS  Google Scholar 

  47. Cao J et al (2008) Boric acid inhibits LPS-induced TNF-α formation through a thiol-dependent mechanism in THP-1 cells. J Trace Elem Med Biol 22(3):189–195

    Article  CAS  PubMed  Google Scholar 

  48. Turkez H et al (2021) Promising potential of boron compounds against glioblastoma: in vitro antioxidant, anti-inflammatory and anticancer studies. Neurochem Int 149:105137

  49. Benderdour M et al (2000) Effects of boron derivatives on extracellular matrix formation. J Trace Elem Med Biol 14(3):168–173

    Article  CAS  PubMed  Google Scholar 

  50. Travers RL, Rennie GC, Newnham RE (1990) Boron and arthritis: the results of a double-blind pilot study. J Nutr Med 1(2):127–132

    Google Scholar 

  51. Boer CG et al (2019) Intestinal microbiome composition and its relation to joint pain and inflammation. Nat Commun 10(1):4881

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Tsai JC et al (2020) Identification and characterization of the intra-articular microbiome in the osteoarthritic knee. Int J Mol Sci 21(22):8618

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Huang Z, Kraus VB (2016) Does lipopolysaccharide-mediated inflammation have a role in OA? Nat Rev Rheumatol 12(2):123–129

    Article  CAS  PubMed  Google Scholar 

  54. Wei Z, Li F, Pi G (2022) Association between gut microbiota and osteoarthritis: a review of evidence for potential mechanisms and therapeutics. Front Cell Infect Microbiol 12:298

    Article  Google Scholar 

  55. Mongkhon J-M et al (2014) Sorbitol-modified hyaluronic acid reduces oxidative stress, apoptosis and mediators of inflammation and catabolism in human osteoarthritic chondrocytes. Inflamm Res 63:691–701

    Article  CAS  PubMed  Google Scholar 

  56. Boileau C et al (2002) The in situ up-regulation of chondrocyte interleukin-1–converting enzyme and interleukin-18 levels in experimental osteoarthritis is mediated by nitric oxide. Arthritis Rheum 46(10):2637–2647

    Article  CAS  PubMed  Google Scholar 

  57. Afonso V et al (2007) Reactive oxygen species and superoxide dismutases: role in joint diseases. Joint Bone Spine 74(4):324–329

    Article  CAS  PubMed  Google Scholar 

  58. Li H et al (2016) Associations between dietary antioxidants intake and radiographic knee osteoarthritis. Clin Rheumatol 35(6):1585–1592

    Article  PubMed  Google Scholar 

  59. Haghighian MK et al (2014) Effects of sesame seed supplementation on lipid profile and oxidative stress biomarkers in patients with knee osteoarthritis. Health Promot Perspect 4(1):90

    Google Scholar 

  60. Ziskoven C et al (2010) Oxidative stress in secondary osteoarthritis: from cartilage destruction to clinical presentation? Orthop Rev 2(2):23

    Google Scholar 

  61. Bhatti F et al (2017) Vitamin E protects rat mesenchymal stem cells against hydrogen peroxide-induced oxidative stress in vitro and improves their therapeutic potential in surgically-induced rat model of osteoarthritis. Osteoarthr Cartil 25(2):321–331

    Article  CAS  Google Scholar 

  62. Davies CM et al (2008) Reactive nitrogen and oxygen species in interleukin-1-mediated DNA damage associated with osteoarthritis. Osteoarthr Cartil 16(5):624–630

    Article  CAS  Google Scholar 

  63. Ince S et al (2012) Protective effect of boric acid against carbon tetrachloride–induced hepatotoxicity in mice. Drug Chem Toxicol 35(3):285–292

    Article  CAS  PubMed  Google Scholar 

Download references

Funding

None.

Author information

Authors and Affiliations

  1. Department of Orthopedics and Traumatology, Denizli State Hospital, Denizli, Turkey

    Koksal Gundogdu

  2. Department of Physiology, Faculty of Medicine, Pamukkale University, Denizli, Turkey

    Gulsah Gundogdu

  3. Department of Analytical Chemistry, Faculty of Pharmacy, Ataturk University, Erzurum, Turkey

    Fatma Demirkaya Miloglu

  4. Department of Histology and Embryology, Faculty of Medicine, Ataturk University, Erzurum, Turkey

    Tuba Demirci

  5. Department of Physiology, Hamidiye International School of Medicine, University of Health Sciences, Istanbul, Turkey

    Seymanur Yılmaz Tascı

  6. Department of Medical Pharmacology, Faculty of Medicine, Ataturk University, Erzurum, Turkey

    A. M. Abd El-Aty

  7. Department of Pharmacology, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt

    A. M. Abd El-Aty

Authors
  1. Koksal Gundogdu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Gulsah Gundogdu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fatma Demirkaya Miloglu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Tuba Demirci
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Seymanur Yılmaz Tascı
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. A. M. Abd El-Aty
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

The study was designed by GG, FDM, and KG. GG, KG, and SYT carried out the experimental studies. Laboratory studies were performed by GG, FDM, and SYT. Histopathology was performed by TD. Data analysis and interpretation of results were performed by GG, FDM, KG, and TD. The paper was drafted by GG, KG, AMA, SYT, and FDM. AMA formal analysis, validation, writing - review & editing. All authors approved the final version of the manuscript.

Corresponding author

Correspondence to Gulsah Gundogdu.

Ethics declarations

Ethics Approval

This study was approved by the Ethics Committee of the Faculty of Medicine (Atatürk University).

Competing Interests

None.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Key Points

1. This study represents the first evidence demonstrating the effectiveness of boric acid (BA) in alleviating symptoms of knee osteoarthritis (KOA) using an experimental rat model.

2. Specifically, BA effectively reduces the levels of inflammatory cytokines, including metalloproteinase-13 (MMP-13), tumor necrosis factor-alpha (TNF-α), and interleukin-1beta (IL-1β), both in the serum and knee joint samples of the experimental KOA rat model.

3. The application of BA through intra-articular (i.a.) administration has been shown to significantly decrease proinflammatory cytokines, as evidenced by histopathological, immunohistochemical, and biochemical analyses, indicating its potential as an alternative treatment option for KOA.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Gundogdu, K., Gundogdu, G., Demirkaya Miloglu, F. et al. Anti-Inflammatory Effects of Boric Acid in Treating Knee Osteoarthritis: Biochemical and Histopathological Evaluation in Rat Model. Biol Trace Elem Res 202, 2744–2754 (2024). https://doi.org/10.1007/s12011-023-03872-0

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12011-023-03872-0

Keywords

Search

Navigation