N.N. Priorov Journal of Traumatology and OrthopedicsN.N. Priorov Journal of Traumatology and OrthopedicsВестник травматологии и ортопедии им. Н.Н. Приорова0869-86782658-6738Eco-Vector65075010.17816/vto650750Original study articlesОригинальные исследованияResearch ArticleOn the mechanism of pharmacological regulation of neoinnervation in the subchondral bone by chondroitin sulfate at late stages of osteoarthritisО механизме фармакологической регуляции неоиннервации в субхондральной кости хондроитин сульфатом на поздних стадиях остеоартритаhttps://orcid.org/0000-0003-1916-38307865-6011MinasovTimur B.МинасовТимур Булатович
Russian Federation

MD

M004@ya.ruhttps://orcid.org/0000-0002-5933-57327308-6756SarvilinaIrina V.СарвилинаИрина Владиславовна
Russian Federation

MD

isarvilina@mail.ruhttps://orcid.org/0000-0002-7663-710X6317-9833GromovaOlga A.ГромоваОльга Алексеевна
Russian Federation

MD

unesco.gromova@gmail.comhttps://orcid.org/0000-0003-1314-28871402-5186NazarenkoAnton G.НазаренкоАнтон Герасимович
Russian Federation

MD, Dr. Sci. (Medicine), professor RAS

д-р мед. наук, профессор РАН

NazarenkoAG@cito.priorov.ruhttps://orcid.org/0000-0002-6736-97726889-8166ZagorodniyNikolay V.ЗагороднийНиколай Васильевич
Russian Federation

MD, Dr. Sci. (Medicine), professor

д-р мед. наук, профессор

zagorodniy@sustav.ruBashkir State Medical UniversityБашкирский государственный медицинский университетLLC Medical Center “Novomeditsina”Медицинский центр «Новомедицина»Federal Research Center “Informatics and Management”Федеральный исследовательский центр «Информатика и управление»Priorov National Medical Research Center for Traumatology and OrthopedicsНациональный медицинский исследовательский центр травматологии и ортопедии им. Н.Н. ПриороваPeoples’ Friendship University of Russia named after Patrice LumumbaРоссийский университет дружбы народов им. Патриса Лумумбы250220251502202532183943101202504022025Copyright ©; 2025, Eco-VectorCopyright ©; 2025, Эко-Вектор2025Eco-VectorЭко-Векторhttps://creativecommons.org/licenses/by-nc-nd/4.0/https://journals.eco-vector.com/0869-8678/article/view/650750

BACKGROUND: Today, the molecular mechanisms of pain development and the role of neoinnervation in the articular cartilage (AC) degradation in osteoarthritis (OA) have been revealed.

AIM: Analysis of the mechanism of pharmacological regulation of chondroitin sulfate (CS) neoinnervation in the subchondral bone (SB) at late stages of OA based on a retrospective analysis of the results of an open prospective controlled randomized study of the effectiveness of highly purified CS in parenteral form in individuals with OA of the knee joint (KJ) stage III according to Kellgren-Lawrence and functional insufficiency of the joints of stage II.

MATERIALS AND METHODS: Total knee arthroplasty (TKR) was performed in 67 patients (24 men and 43 women, aged 41 to 73 years) with knee OA in two groups: the control group (CG; n=35) and the main group (MG; n=32). All patients received non-steroidal anti-inflammatory drugs at a standard daily dose upon inclusion in the study. MG patients additionally received a parenteral form of CS, a course of 25 injections for 50 days, 2 months before TKR (according to C. Ranawat). X-ray of the knee was performed. The innervation of the joint tissues was studied using biosamples of the SC, SC, and the joint capsule obtained during TKR: histopathological assessment of the synovial membrane according to GSS, histological assessment, histochemical assessment of the SC according to H. Mankin as modified by V.B. Kraus et al., on the OARSI scale. An enzyme immunoassay was performed on the blood levels at visits 0, 1, and 2: C-reactive protein (CRP), interleukin-6 (IL-6), nerve growth factor β (βNGF), calcitonin gene-related peptide (CGRP), potassium, and calcium.

RESULTS: In patients in the CG, a significant number of capillary loops were found in the AC from the SC side and nerve endings in the AC thickness. In the MG, along with adaptive restructuring, the absence of neoangiogenesis from the SC side and neoinnervation in the AC thickness was shown. At discharge from the hospital and 3 months after TKR, a significant decrease in βNGF, CGRP, VEGF, CRP, IL-6, potassium and calcium in the blood of patients in the MG was recorded.

CONCLUSION: The effectiveness of parenteral HS (Chondroguard®) in relation to OA progression may be due to its effect on neoinnervation and is a new direction in therapeutic targeting of OA.

Обоснование. Cегодня раскрыты молекулярные механизмы развития боли и роль неоиннервации в деградации суставного хряща (СХ) при остеоартрите (ОА).

Цель. Анализ механизма фармакологической регуляции хондроитина сульфата (ХС) неоиннервации в субхондральной кости (СК) на поздних стадиях ОА на основе ретроспективного анализа результатов открытого проспективного контролируемого рандомизированного исследования эффективности высокоочищенного ХС в парентеральной форме у лиц с ОА коленного сустава (КС) III стадии по Kellgren–Lawrence и функциональной недостаточностью суставов II степени.

Материалы и методы. Операция тотального эндопротезирования коленного сустава (ТЭКС) выполнена 67 пациентам (24 мужчины и 43 женщины 41–73 лет) с ОА КС в двух группах: контрольной (КГ; n=35) и основной (ОГ; n=32). Все пациенты при включении в исследование получали нестероидные противовоспалительные препараты в стандартной суточной дозе. Пациенты ОГ дополнительно получали парентеральную форму ХС, курс 25 инъекций 50 дней, за 2 месяца до проведения ТЭКС (по C. Ranawat). Проводилась рентгенография КС. Изучали иннервацию суставных тканей пациентов по биообразцам СК, СХ, суставной капсулы, полученным в ходе ТЭКС: гистопатологическая оценка синовиальной оболочки по GSS, гистологическая оценка, гистохимическая оценка СХ по H. Mankin в модификации V.B. Kraus и соавт., по шкале OARSI. Проведён иммуноферментный анализ содержания в крови на визитах 0, 1 и 2 С-реактивного белка, интерлейкина-6 (ИЛ-6), фактора роста нервов β (βNGF), кальцитонин-ген-родственного пептида (CGRP), калия и кальция.

Результаты. У пациентов в КГ выявлено значительное количество капиллярных петель в СХ со стороны СК и нервных окончаний в толще СХ. В ОГ вместе с адаптивной перестройкой выявлено отсутствие неоангиогенеза со стороны СК и неоиннервации в толще СХ. При выписке из стационара и через 3 месяца после ТЭКС регистрировали значимое снижение βNGF, CGRP, VEGF, СРБ, ИЛ-6, калия и кальция в крови пациентов ОГ.

Заключение. Эффективность ХС в парентеральной форме (Хондрогард®) в отношении прогрессирования ОА может быть обусловлена его эффектом в отношении неоиннервации и является новым направлением терапевтического таргетирования ОА.

osteoarthritissubchondral boneneoinnervationmorphologybiomarkerschondroitin sulfateChondroguardостеоартритсубхондральная костьнеоиннервацияморфологиябиомаркерыхондроитина сульфатХондрогардGBD 2021 Osteoarthritis Collaborators. Global, regional, and national burden of osteoarthritis, 1990–2020 and projections to 2050: a systematic analysis for the Global Burden of Disease Study 2021. Lancet Rheumatol. 2023;5(9):e508–22. doi: 10.1016/S2665-9913(23)00163-7Weng Q, Chen Q, Jiang T, et al. Global burden of early-onset osteoarthritis, 1990–2019: results from the Global Burden of Disease Study 2019. Ann Rheum Dis. 2024;83(7):915–25. doi: 10.1136/ard-2023-225324Brandt KD. Pain, synovitis, and articular cartilage changes in osteoarthritis. Semin Arthritis Rheum. 1989;18(4 Suppl 2):77–80. doi: 10.1016/0049-0172(89)90021-8Altman RD, Dean D. Pain in osteoarthritis. Introduction and overview. Semin Arthritis Rheum. 1989;18(4 Suppl 2):1–3. doi: 10.1016/0049-0172(89)90007-3Kidd BL, Mapp PI, Blake DR, Gibson SJ, Polak JM. Neurogenic influences in arthritis. Ann Rheum Dis. 1990;49(8):649–52. doi: 10.1136/ard.49.8.649Hukkanen M, Grönblad M, Rees R, et al. Regional distribution of mast cells and peptide containing nerves in normal and adjuvant arthritic rat synovium. J Rheumatol. 1991;18(2):177–83.Saito T, Koshino T. Distribution of neuropeptides in synovium of the knee with osteoarthritis. Clin Orthop Relat Res. 2000;(376):172–82. doi: 10.1097/00003086-200007000-00024Saxler G, Löer F, Skumavc M, Pförtner J, Hanesch U. Localization of SP- and CGRP-immunopositive nerve fibers in the hip joint of patients with painful osteoarthritis and of patients with painless failed total hip arthroplasties. Eur J Pain. 2007;11(1):67–74. doi: 10.1016/j.ejpain.2005.12.011Englund M, Niu J, Guermazi A, et al. Effect of meniscal damage on the development of frequent knee pain, aching, or stiffness. Arthritis Rheum. 2007;56(12):4048–54. doi: 10.1002/art.23071Felson DT, Niu J, Guermazi A, et al. Correlation of the development of knee pain with enlarging bone marrow lesions on magnetic resonance imaging. Arthritis Rheum. 2007;56(9):2986–92. doi: 10.1002/art.22851Roemer FW, Guermazi A, Javaid MK, et al.; MOST Study investigators. Change in MRI-detected subchondral bone marrow lesions is associated with cartilage loss: the MOST Study. A longitudinal multicentre study of knee osteoarthritis. Ann Rheum Dis. 2009;68(9):1461–5. doi: 10.1136/ard.2008.096834Ritter AM, Lewin GR, Kremer NE, Mendell LM. Requirement for nerve growth factor in the development of myelinated nociceptors in vivo. Nature. 1991;350(6318):500–2. doi: 10.1038/350500a0Levi-Montalcini R. Growth control of nerve cells by a protein factor and its antiserum: discovery of this factor may provide new leads to understanding of some neurogenetic processes. Science. 1964;143(3602):105–10. doi: 10.1126/science.143.3602.105Woolf CJ, Safieh-Garabedian B, Ma QP, Crilly P, Winter J. Nerve growth factor contributes to the generation of inflammatory sensory hypersensitivity. Neuroscience. 1994;62(2):327–31. doi: 10.1016/0306-4522(94)90366-2McMahon SB, Bennett DL, Priestley JV, Shelton DL. The biological effects of endogenous nerve growth factor on adult sensory neurons revealed by a trkA-IgG fusion molecule. Nat Med. 1995;1(8):774–80. doi: 10.1038/nm0895-774von Loga IS, El-Turabi A, Jostins L, et al. Active immunisation targeting nerve growth factor attenuates chronic pain behaviour in murine osteoarthritis. Ann Rheum Dis. 2019;78(5):672–675. doi: 10.1136/annrheumdis-2018-214489Lane NE, Schnitzer TJ, Birbara CA, et al. Tanezumab for the treatment of pain from osteoarthritis of the knee. N Engl J Med. 2010;363(16):1521–31. doi: 10.1056/NEJMoa0901510Walsh DA, McWilliams DF, Turley MJ, et al. Angiogenesis and nerve growth factor at the osteochondral junction in rheumatoid arthritis and osteoarthritis. Rheumatology (Oxford). 2010;49(10):1852–61. doi: 10.1093/rheumatology/keq188Aso K, Shahtaheri SM, Hill R, et al. Associations of Symptomatic Knee Osteoarthritis With Histopathologic Features in Subchondral Bone. Arthritis Rheumatol. 2019;71(6):916–924. doi: 10.1002/art.40820Driscoll C, Chanalaris A, Knights C, et al. Nociceptive Sensitizers Are Regulated in Damaged Joint Tissues, Including Articular Cartilage, When Osteoarthritic Mice Display Pain Behavior. Arthritis Rheumatol. 2016;68(4):857–67. doi: 10.1002/art.39523Miller RE, Tran PB, Das R, et al. CCR2 chemokine receptor signaling mediates pain in experimental osteoarthritis. Proc Natl Acad Sci U S A. 2012. 11;109(50):20602–7. doi: 10.1073/pnas.1209294110Obeidat AM, Wood MJ, Adamczyk NS, et al. Piezo2 expressing nociceptors mediate mechanical sensitization in experimental osteoarthritis. Nat Commun. 2023;14(1):2479. doi: 10.1038/s41467-023-38241-xConaghan PG, Cook AD, Hamilton JA, Tak PP. Therapeutic options for targeting inflammatory osteoarthritis pain. Nat Rev Rheumatol. 2019;15(6):355–363. doi: 10.1038/s41584-019-0221-yWenham CY, Hensor EM, Grainger AJ, et al. A randomized, double-blind, placebo-controlled trial of low-dose oral prednisolone for treating painful hand osteoarthritis. Rheumatology (Oxford). 2012;51(12):2286–94. doi: 10.1093/rheumatology/kes219Kroon FPB, Kortekaas MC, Boonen A, et al. Results of a 6-week treatment with 10 mg prednisolone in patients with hand osteoarthritis (HOPE): a double-blind, randomised, placebo-controlled trial. Lancet. 2019. 30;394(10213):1993–2001. doi: 10.1016/S0140-6736(19)32489-4Watson M. The suppressing effect of indomethacin on articular cartilage. Rheumatol Rehabil. 1976;15(1):26–30. doi: 10.1093/rheumatology/15.1.26Slowman-Kovacs SD, Albrecht ME, Brandt KD. Effects of salicylate on chondrocytes from osteoarthritic and contralateral knees of dogs with unilateral anterior cruciate ligament transection. Arthritis Rheum. 1989;32(4):486–90. doi: 10.1002/anr.1780320420Palmoski MJ, Colyer RA, Brandt KD. Marked suppression by salicylate of the augmented proteoglycan synthesis in osteoarthritic cartilage. Arthritis Rheum. 1980;23(1):83–91. doi: 10.1002/art.1780230114Palmoski MJ, Brandt KD. In vivo effect of aspirin on canine osteoarthritic cartilage. Arthritis Rheum. 1983;26(8):994–1001. doi: 10.1002/art.1780260808McAlindon TE, LaValley MP, Harvey WF, et al. Effect of Intra-articular Triamcinolone vs Saline on Knee Cartilage Volume and Pain in Patients With Knee Osteoarthritis: A Randomized Clinical Trial. JAMA. 2017;317(19):1967–1975. doi: 10.1001/jama.2017.5283Vincent TL, Miller RE. Molecular pathogenesis of OA pain: Past, present, and future. Osteoarthritis Cartilage. 2024;32(4):398–405. doi: 10.1016/j.joca.2024.01.005Hochberg M. Structure-modifying effects of chondroitin sulfate in knee osteoarthritis: an updated meta-analysis of randomized placebo-controlled trials of 2-year duration. Osteoarthritis Cartilage. 2010;18 Suppl 1:S28–31. doi: 10.1016/j.joca.2010.02.016.Torshin IYu, Lila AM, Naumov AV, et al. Meta-analysis of clinical trials of osteoarthritis treatment effectiveness with Chondroguard. Farmakoekonomika. Modern Pharmacoeconomics and Pharmacoepidemiology. 2020;13(4):388–399. (in Russ.). doi: 10.17749/2070-4909/farmakoekonomika.2020.066Reginster J-Y, Veronese N. Highly purified chondroitin sulfate: a literature review on clinical efficacy and pharmacoeconomic aspects in osteoarthritis treatment. Aging Clin Exp Res. 2021;33(1):37–47. doi: 10.1007/s40520-020-01643-8Monfort J, Pelletier J, Garcia-Giralt N, Martel-Pelletier J. Biochemical basis of the effect of chondroitin sulphate on osteoarthritis articular tissues. Ann Rheum Dis. 2008;67(6):735–740. doi: 10.1136/ard.2006.068882Martel-Pelletier J, Kwan Tat S, Pelletier J. Effects of chondroitin sulfate in the pathophysiology of the osteoarthritic joint: a narrative review. Osteoarthritis Cartilage. 2010;18 Suppl 1:S7–11. doi: 10.1016/j.joca.2010.01.015Lambert C, Mathy-Hartert M, Dubuc J, et al. Characterization of synovial angiogenesis in osteoarthritis patients and its modulation by chondroitin sulfate. Arthritis Res Ther. 2012;14(2):R58. doi: 10.1186/ar3771.Minasov TB, Lila AM, Nazarenko AG, et al. Morphological reflection of highly purified chondroitin sulfate action in patients with decompensated form of knee osteoarthritis. Modern Rheumatology Journal. 2022;16(6):55–63 (in Russ.). doi: 10.14412/1996-7012-2022-6-55-63Anijs Th, Wolfson D, Verdonschot N, Janssen D. Population-based effect of total knee arthroplasty alignment on simulated tibial bone remodeling. J Mech Behav Biomed Mater. 2020;111:104014. doi: 10.1016/j.jmbbm.2020.104014Dubrovin GM, Lebedev AYu. Prediction and prevention of the development of post-traumatic gonarthrosis in intra-articular fractures of the knee joint. Khirurgiya. Zhurnal im. N.I. Pirogova. 2018;(12):106–10. (In Russ.). doi: 10.17116/hirurgia2018121106Martel-Pelletier J, Barr A, Cicuttini F, et al. Osteoarthritis. Nat Rev Dis Primers. 2016;2:16072. doi: 10.1038/nrdp.2016.72Nasonov EL, editor. Rossiiskie klinicheskie rekomendatsii. Revmatologiya. Moscow: GEOTAR-Media; 2017. 464 p. (In Russ.).Ranawat C, Dorr L, Inglis A. Total hip arthroplasty in protrusio acetabuli of rheumatoid arthritis. J Bone Joint Surg Am. 1980;62(7):1059–65Krenn V, Morawietz L, Burmester GR, et al. Synovitis score: discrimination between chronic low-grade and high-grade synovitis. Histopathology. 2006;49(4):358–64. doi: 10.1111/j.1365-2559.2006.02508.xBade M, Kohrt W, Stevens-Lapsley J. Outcomes before and after total knee arthroplasty compared to healthy adults. J Orthop Sports Phys Ther. 2010;40(9):559–67. doi: 10.2519/jospt.2010.3317Bourne R, Chesworth B, Davis A, et al. Patient satisfaction after total knee arthroplasty: who is satisfied and who is not? Clin Orthop Relat Res. 2010;468(1):57–63. doi: 10.1007/ s11999-009-1119-9Balaboshka KB, Khadzkou YK. The analysis of the early total knee joint arthroplasty results. Vestnik VGMU. 2017;16(5):75–83. (In Russ.). doi: 10.22263/2312-4156.2017.5.75Sarvilina IV, Minasov TB, Lila AM, et al. On the efficacy of the parenteral form of highly purified chondroitin sulfate in the mode of perioperative preparation for total knee arthroplasty. RMJ. 2022;7:7–16. (in Russ.). EDN: FDDFLKMertens M, Singh J. Biomarkers in arthroplasty: a systematic review. Open Orthop J. 2011:5:92–105. doi: 10.2174/1874325001105010092Pearle A, Scanzello C, George S, et al. Elevated high-sensitivity C-reactive protein levels are associated with local inflammatory findings in patients with osteoarthritis. Osteoarthritis Cartilage. 2007;15(5):516–523. doi: 10.1016/j.joca.2006.10.010Koch A, Harlow L, Haines G, et al. Vascular endothelial growth factor. A cytokine modulating endothelial function in rheumatoid arthritis. J Immunol. 1994;152(8):4149–4156.Barthel C, Yeremenko N, Jacobs R, et al. Nerve growth factor and receptor expression in rheumatoid arthritis and spondyloarthritis. Arthritis Res Ther. 2009;11(3):R82. doi: 10.1186/ar2716Minasov TB, Sarvilina IV, Lila AM, et al. Remodelirovanie subhondral’noj kosti i neoangiogenez pri dekompensirovannoj forme osteoartrita: evolyuciya terapevticheskogo targetirovaniya. RMJ. 2023;8:8–14. (in Russ.). EDN: BKNEMOIannone F, De Bari C, Dell’Accio F, et al. Increased expression of nerve growth factor (NGF) and high affinity NGF receptor (p140 TrkA) in human osteoarthritic chondrocytes. Rheumatology (Oxford). 2002;41(12):1413–8. doi: 10.1093/rheumatology/41.12.1413Vincent TL. Peripheral pain mechanisms in osteoarthritis. Pain. 2020;161 Suppl 1(1):S138–S146. doi: 10.1097/j.pain.0000000000001923Malfait AM, Miller RE, Block JA. Targeting neurotrophic factors: Novel approaches to musculoskeletal pain. Pharmacol Ther. 2020;211:107553. doi: 10.1016/j.pharmthera.2020.107553Aso K, Shahtaheri SM, Hill R, et al. Contribution of nerves within osteochondral channels to osteoarthritis knee pain in humans and rats. Osteoarthritis Cartilage. 2020;28(9):1245–1254. doi: 10.1016/j.joca.2020.05.010Obeidat AM, Miller RE, Miller RJ, Malfait AM. The nociceptive innervation of the normal and osteoarthritic mouse knee. Osteoarthritis Cartilage. 2019;27(11):1669–1679. doi: 10.1016/j.joca.2019.07.012Obeidat AM, Ishihara S, Li J, et al. Intra-articular sprouting of nociceptors accompanies progressive osteoarthritis: comparative evidence in four murine models. Front Neuroanat. 2024;18:1429124. doi: 10.3389/fnana.2024.1429124Zhu S, Zhu J, Zhen G, et al. Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain. J Clin Invest. 2019;129(3):1076–1093. doi: 10.1172/JCI121561Olaseinde OF, Owoyele BV. Chondroitin sulfate produces antinociception and neuroprotection in chronic constriction injury-induced neuropathic pain in rats by increasing anti-inflammatory molecules and reducing oxidative stress. Int J Health Sci (Qassim). 2021;15(5):3–17.