Research progress on the causes of pain in knee osteoarthritis_Chinese Journal of Reparative and Reconstructive Surgery

Authors：

WEI Ning ,  ZHENG Zhanle

Knee Preservation Center, Hebei Medical University Third Hospital, Hebei Provincial Key Laboratory of Orthopaedic Biomechanics, Shijiazhuang Hebei, 050051, P. R. China;

Corresponding?author：

ZHENG Zhanle, Email: 38200671@hebmu.edu.cn

Keywords：

Knee osteoarthritis; pain; cause of illness; inflammation; neural regulation; biomechanics

DOI：

10.7507/1002-1892.202508009

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To review the research progress related to pain in knee osteoarthritis (KOA). Methods A systematic review of relevant research literature at home and abroad in recent years was conducted to analyze the roles played by multi-dimensional factors such as demographics, imaging, serology, bone metabolism, biomechanics, neurological factors, and macrophages in the occurrence and development of KOA pain. The mechanisms of pain induction were expounded and the research directions were prospectively proposed. Results The occurrence of KOA pain is a complex process interwoven with multiple factors. Demographic factors such as gender, age, and body weight are closely related to its occurrence and pain degree. Structural changes shown by imaging examinations (such as MRI, ultrasound, and X-ray films) can be used to assess the level of pain. A variety of inflammatory factors released by intra-articular inflammation directly participate in the initiation of pain. Bone metabolic factors can also induce pain by influencing changes in bone density. Biomechanical factors are involved in the pain process by altering the concentrated distribution of joint stress. The various mediators released by the local inflammatory response of the joint trigger hyperalgesia and peripheral nerve sensitization through pain receptors, promoting the conduction and amplification of pain signals. The bidirectional interaction between nerves and joints further intensifies the pain. In addition, the expression of certain ion channels, the mediation and release of pain signals by macrophages and osteoclasts, provide a theoretical direction for in-depth exploration of the microscopic mechanism of KOA pain. Conclusion Future research needs to integrate multiple regulatory mechanisms such as biomechanics, inflammation and neural regulation, systematically explore key intervention targets, in order to deepen the understanding of the pain mechanism of KOA and promote the formation of more comprehensive and precise pain diagnosis and treatment plans.

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7.	Hunter DJ, Bierma-Zeinstra S. Osteoarthritis. Lancet, 2019, 393(10182): 1745-1759.
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1. Neogi T. The epidemiology and impact of pain in osteoarthritis. Osteoarthritis Cartilage, 2013, 21(9): 1145-1153.
2. Abramoff B, Caldera FE. Osteoarthritis: pathology, diagnosis, and treatment options. Med Clin North Am, 2020, 104(2): 293-311.
3. Li Y, Yang Y, Guo J, et al. Spinal NF-kB upregulation contributes to hyperalgesia in a rat model of advanced osteoarthritis. Mol Pain, 2020, 16: 1744806920905691. doi: 10.1177/1744806920905691.
4. Neogi T. The epidemiology and impact of pain in osteoarthritis. Osteoarthritis Cartilage, 2013, 21(9): 1145-1153.
5. Gholami Z, Faezi ST, Letafatkar A, et al. Pain neuroscience education, blended exercises and booster sessions as an effective therapy for pain, functional and psychological factors in patients with knee osteoarthritis: a study protocol for a single-blind randomised controlled trial with 22 factorial design during 6-month follow-up. BMJ Open, 2023, 13(5): e070336. doi: 10.1136/bmjopen-2022-070336.
6. Silverwood V, Blagojevic-Bucknall M, Jinks C, et al. Current evidence on risk factors for knee osteoarthritis in older adults: a systematic review and meta-analysis. Osteoarthritis Cartilage, 2015, 23(4): 507-515.
7. Hunter DJ, Bierma-Zeinstra S. Osteoarthritis. Lancet, 2019, 393(10182): 1745-1759.
8. Zhang Y, Jordan JM. Epidemiology of osteoarthritis. Rheum Dis Clin North (Am), 2008, 34(3): 515-529.
9. O'Connor MI. Sex differences in osteoarthritis of the hip and knee. J Am Acad Orthop Surg, 2007, 15 Suppl 1: S22-S25.
10. Dai X, Ying P, Ding W, et al. Genetic estrogen receptor alpha gene PvuⅡ polymorphism in susceptibility to knee osteoarthritis in a Chinese Han population: A southern Jiangsu study. Knee, 2020, 27(3): 803-808.
11. Zhao H, Yu F, Wu W. The mechanism by which estrogen level affects knee osteoarthritis pain in perimenopause and non-pharmacological measures. Int J Mol Sci, 2025, 26(6): 2391. doi: 10.3390/ijms26062391.
12. Mermerci BB, Garip Y, Uysal RS, et al. Clinic and ultrasound findings related to pain in patients with knee osteoarthritis. Clin Rheumatol, 2011, 30(8): 1055-1062.
13. Vincent HK, Heywood K, Connelly J, et al. Obesity and weight loss in the treatment and prevention of osteoarthritis. PM R, 2012, 4(5 Suppl): S59-S67.
14. Schrager MA, Metter EJ, Simonsick E, et al. Sarcopenic obesity and inflammation in the InCHIANTI study. J Appl Physiol (1985), 2007, 102(3): 919-925.
15. 何家俊, 周盟, 李圓浩, 等. 肥胖對急性胰腺炎作用的研究進展. 中華臨床醫師雜志(電子版), 2019, 13(7): 548-551.
16. McNulty AL, Miller MR, O'Connor SK, et al. The effects of adipokines on cartilage and meniscus catabolism. Connect Tissue Res, 2011, 52(6): 523-533.
17. Primrose JG, Jain L, Bolam SM, et al. Concentration-dependent effects of leptin on osteoarthritis-associated changes in phenotype of human chondrocytes. Connect Tissue Res, 2023, 64(5): 457-468.
18. Rogers MW, Wilder FV. The association of BMI and knee pain among persons with radiographic knee osteoarthritis: a cross-sectional study. BMC Musculoskelet Disord, 2008, 9: 163. doi: 10.1186/1471-2474-9-163.
19. de Miguel Mendieta E, Cobo Ibá?ez T, Usón Jaeger J, et al. Clinical and ultrasonographic findings related to knee pain in osteoarthritis. Osteoarthritis Cartilage, 2006, 14(6): 540-544.
20. Hill CL, Gale DR, Chaisson CE, et al. Periarticular lesions detected on magnetic resonance imaging: prevalence in knees with and without symptoms. Arthritis Rheum, 2003, 48(10): 2836-2844.
21. Monteforte P, Rovetta G. Sonographic assessment of soft tissue alterations in osteoarthritis of the knee. Int J Tissue React, 1999, 21(1): 19-23.
22. Monteforte P, Rovetta G. Sonographic assessment of soft tissue alterations in osteoarthritis of the knee. Int J Tissue React, 1999, 21(1): 19-23.
23. de Miguel Mendieta E, Cobo Ibá?ez T, Usón Jaeger J, et al. Clinical and ultrasonographic findings related to knee pain in osteoarthritis. Osteoarthritis Cartilage, 2006, 14(6): 540-544.
24. Zhao Z, Zhao M, Yang T, et al. Identifying significant structural factors associated with knee pain severity in patients with osteoarthritis using machine learning. Sci Rep, 2024, 14(1): 14705. doi: 10.1038/s41598-024-65613-0.
25. Stannus OP, Jones G, Blizzard L, et al. Associations between serum levels of inflammatory markers and change in knee pain over 5 years in older adults: a prospective cohort study. Ann Rheum Dis, 2013, 72(4): 535-540.
26. Yang Y, Hao C, Jiao T, et al. Osteoarthritis treatment via the GLP-1-mediated gut-joint axis targets intestinal FXR signaling. Science, 2025, 388(6742): eadt0548. doi: 10.1126/science.adt0548.
27. Longo UG, Lalli A, Bandini B, et al. Role of the gut microbiota in osteoarthritis, rheumatoid arthritis, and spondylarthritis: an update on the gut-joint axis. Int J Mol Sci, 2024, 25(6): 3242. doi: 10.3390/ijms25063242.
28. Li X, Ellman M, Muddasani P, et al. Prostaglandin E2 and its cognate EP receptors control human adult articular cartilage homeostasis and are linked to the pathophysiology of osteoarthritis. Arthritis Rheum, 2009, 60(2): 513-523.
29. Arendt-Nielsen L, Eskehave TN, Egsgaard LL, et al. Association between experimental pain biomarkers and serologic markers in patients with different degrees of painful knee osteoarthritis. Arthritis Rheumatol, 2014, 66(12): 3317-3326.
30. Liu L, Tian F, Li GY, et al. The effects and significance of gut microbiota and its metabolites on the regulation of osteoarthritis: Close coordination of gut-bone axis. Front Nutr, 2022, 9: 1012087. doi: 10.3389/fnut.2022.1012087.
31. Yang D, Chen Y, Guo J, et al. The organ-joint axes in osteoarthritis: significant pathogenesis and therapeutic targets. Aging Dis, 2024, 16(5): 2999-3021.
32. Sun C, Zhou X, Guo T, et al. The immune role of the intestinal microbiome in knee osteoarthritis: a review of the possible mechanisms and therapies. Front Immunol, 2023, 14: 1168818. doi: 10.3389/fimmu.2023.1168818.
33. Mündermann A, Nüesch C, Ewald H, et al. Osteoarthritis year in review 2024: Biomechanics. Osteoarthritis Cartilage, 2024, 32(12): 1530-1541.
34. Fowler-Brown A, Kim DH, Shi L, et al. The mediating effect of leptin on the relationship between body weight and knee osteoarthritis in older adults. Arthritis Rheumatol, 2015, 67(1): 169-175.
35. 高蓉琳, 蒲金呈, 韓放, 等. 代謝性炎癥在骨關節炎發生發展中的作用與治療現狀. 同濟大學學報(醫學版), 2024, 45(1): 130-136.
36. 孫鏞奇, 郭克淳, 劉澤中, 等. 骨代謝水平與膝骨關節炎疼痛的臨床相關性研究. 中國骨傷, 2025, 38(5): 482-486.
37. Diamond LE, Grant T, Uhlrich SD. Osteoarthritis year in review 2023: Biomechanics. Osteoarthritis Cartilage, 2024, 32(2): 138-147.
38. Sutton AJ, Muir KR, Mockett S, Fentem P. A case-control study to investigate the relation between low and moderate levels of physical activity and osteoarthritis of the knee using data collected as part of the Allied Dunbar National Fitness Survey. Ann Rheum Dis, 2001, 60(8): 756-64.
39. Hutchison L, Grayson J, Hiller C, et al. Relationship between knee biomechanics and pain in people with knee osteoarthritis: a systematic review and meta-analysis. Arthritis Care Res (Hoboken), 2023, 75(6): 1351-1361.
40. Chang A, Hurwitz D, Dunlop D, et al. The relationship between toe-out angle during gait and progression of medial tibiofemoral osteoarthritis. Ann Rheum Dis, 2007, 66(10): 1271-1275.
41. Martínez-Moreno D, Jiménez G, Gálvez-Martín P, et al. Cartilage biomechanics: A key factor for osteoarthritis regenerative medicine. Biochim Biophys Acta Mol Basis Dis, 2019, 1865(6): 1067-1075.
42. Morgan M, Nazemian V, Harrington K, et al. Mini review: The role of sensory innervation to subchondral bone in osteoarthritis pain. Front Endocrinol (Lausanne), 2022, 13: 1047943. doi: 10.3389/fendo.2022.1047943.
43. Wise BL, Seidel MF, Lane NE. The evolution of nerve growth factor inhibition in clinical medicine. Nat Rev Rheumatol, 2021, 17(1): 34-46.
44. Obeidat 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-x.
45. Mickle AD, Shepherd AJ, Mohapatra DP. Sensory TRP channels: the key transducers of nociception and pain. Prog Mol Biol Transl Sci, 2015, 131: 73-118.
46. Mickle AD, Shepherd AJ, Mohapatra DP. Sensory TRP channels: the key transducers of nociception and pain. Prog Mol Biol Transl Sci, 2015, 131: 73-118.
47. O'Neill TW, Felson DT. Mechanisms of osteoarthritis (OA) pain. Curr Osteoporos Rep, 2018, 16(5): 611-616.
48. Koivisto AP, Belvisi MG, Gaudet R, et al. Advances in TRP channel drug discovery: from target validation to clinical studies. Nat Rev Drug Discov, 2022, 21(1): 41-59.
49. La Hausse De Lalouviere L, Morice O, Fitzgerald M. Altered sensory innervation and pain hypersensitivity in a model of young painful arthritic joints: short- and long-term effects. Inflamm Res, 2021, 70(4): 483-493.
50. Woolf CJ. Central sensitization: implications for the diagnosis and treatment of pain. Pain, 2011, 152(3 Suppl): S2-S15.
51. Schaible HG, K?nig C, Ebersberger A. Spinal pain processing in arthritis: Neuron and glia (inter)actions. J Neurochem, 2024, 168(11): 3644-3662.
52. Raoof R, Martin Gil C, Lafeber FPJG, et al. Dorsal root ganglia macrophages maintain osteoarthritis pain. J Neurosci, 2021, 41(39): 8249-8261.
53. Geraghty T, Obeidat AM, Ishihara S, et al. Age-associated changes in knee osteoarthritis, pain-related behaviors, and dorsal root ganglia immunophenotyping of male and female mice. Arthritis Rheumatol, 2023, 75(10): 1770-1780.
54. Miller RE, Miller RJ, Malfait AM. Osteoarthritis joint pain: the cytokine connection. Cytokine, 2014, 70(2): 185-193.
55. Alsaloum M, Higerd GP, Effraim PR, et al. Status of peripheral sodium channel blockers for non-addictive pain treatment. Nat Rev Neurol, 2020, 16(12): 689-705.
56. Yang Y, Huang J, Mis MA, et al. Nav1. 7-A1632G mutation from a family with inherited erythromelalgia: enhanced firing of dorsal root ganglia neurons evoked by thermal stimuli. J Neurosci, 2016, 36(28): 7511-7522.
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