CD19, ALDH18A1, and CACNA1G as Significant Hub Genes in End-Stage Osteoarthritis
Abstract
Background: Osteoarthritis is one of the principal causes of chronic joint disease and may progressively engender disability in elderly individuals. The present study aimed to identify differentially expressed genes and associated signaling pathways in end-stage osteoarthritis.
Methods: Differentially expressed messenger RNAs in the early and end stages of osteoarthritis were examined through gene expression omnibus 2R (GEO2R) in the GSE32317 dataset. Subsequently, gene ontology (GO) enrichment, Kyoto Encyclopedia of Genes and Genomes (KEGG), and protein-protein interaction (PPI) analyses were conducted. Furthermore, microRNAs targeting hub genes were investigated using the miRcode database. This study was conducted jointly at Bam University of Medical Sciences and Rajaie Cardiovascular, Medical and Research Center on October 2022.
Results: Differentially expressed data demonstrated downregulation in 134 genes and upregulation in 189 genes in end-stage knee osteoarthritis. The results of the enrichment and PPI analyses determined 4 end-stage knee osteoarthritis-related hub genes: IL-1B, CD19, CACNA1G, and ALDH18A1. The knee osteoarthritis-related key genes were involved in the Wnt signaling, B cell receptor signaling, calcium signaling, circadian entrainment, arginine and proline metabolism, axon guidance, and cytokine-cytokine receptor pathways. Additionally, the microRNAs targeting the 4 aforementioned genes were predicted.
Conclusion: The present study is the first to provide fresh insights into the potential therapeutic targets of key genes, namely CD19, CACNA1G, and ALDH18A1, differentially expressed in end-stage osteoarthritis and their relevant signaling pathways and interactive microRNAs.
1. Filardo G, Kon E, Longo UG, et al (2016). Non-surgical treatments for the management of early osteoarthritis. KSSTA,24(6):1775-85.
2. Goldring MB (2012). Articular cartilage degradation in osteoarthritis. SAGE Publications Sage CA: Los Angeles, CA, 8(1): 7–9.
3. Sandell LJ (2012). Etiology of osteoarthritis: genetics and synovial joint development. Nat. Rev. Rheumatol, 8(2):77-89.
4. Chen D, Shen J, Zhao W, Wang T, Han L, Hamilton JL, et al (2017). Osteoarthritis: toward a comprehensive understanding of pathological mechanism. Bone Res,5(1):1-13.
5. Lotz M, Loeser RF (2012). Effects of aging on articular cartilage homeostasis. Bone, 51(2):241-8.
6. Chang L, Liu A, Xu J, Xu X, Dai J, Wu R, et al (2021). TDP-43 maintains chondrocyte homeostasis and alleviates cartilage degradation in osteoarthritis. Osteoarthr. Cartil,29(7):1036-47.
7. Polyakova J, Zavodovsky B, Seewordova L, Akhverdyan Y, Zborovskaya I (2015). THU0476 Pathogenic Relationship Between Osteoarthritis, Overweight and Inflammation. BMJ Publishing Group Ltd, 74(2).
8. Bos SD, Slagboom PE, Meulenbelt I (2008). New insights into osteoarthritis: early developmental features of an ageing-related disease. Curr Opin Rheumatol, 20(5):553-9.
9. Kang Y-J, Yoo J-I, Baek K-W. Differential gene expression profile by RNA sequencing study of elderly osteoporotic hip fracture patients with sarcopenia (2021). J. Orthop. Translat, 29:10-8.
10. Malakootian M, Gholipour A, Bagheri Moghaddam M, Arabian M, Oveisee M (2022). Potential roles of circular rnas and environmental and clinical factors in intervertebral disc degeneration. Environ. Health Eng. Manag, 9(2):189-200.
11. Chang L, Yao H, Yao Z, Ho KK-W, Ong MT-Y, Dai B, et al (2021). Comprehensive analysis of key genes, signaling pathways and miRNAs in human knee osteoarthritis: based on bioinformatics. Front. pharmacol,2237.
12. Ramos YF, den Hollander W, Bovée JV, Bomer N, van der Breggen R, Lakenberg N, et al (2014). Genes involved in the osteoarthritis process identified through genome wide expression analysis in articular cartilage; the RAAK study. PloS one, 9(7):e103056.
13. Malakootian M, Soveizi M, Gholipour A, Oveisee M (2023).Pathophysiology, Diagnosis, Treatment, and Genetics of Carpal Tunnel Syndrome: A Review. Cell. Mol. Neurobiol, 43(5):1817-1831.
14. Cui S, Zhang X, Hai S, Lu H, Chen Y, Li C, et al (2015). Molecular mechanisms of osteoarthritis using gene microarrays. Acta histochemica, 117(1):62-8.
15. Feng Z, Lian K (2015). Identification of genes and pathways associated with osteoarthritis by bioinformatics analyses. Eur Rev Med Pharmacol Sci, 19(5):736-44.
16. Zhen G, Wen C, Jia X, Li Y, Crane JL, Mears SC, et al (2013). Inhibition of TGF–β signaling in subchondral bone mesenchymal stem cells attenuates osteoarthritis. Nat. Med, 19(6):704.
17. Van Der Kraan PM (2017). The changing role of TGFβ in healthy, ageing and osteoarthritic joints. Nat. Rev. Rheumatol, 13(3):155-63.
18. McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis (2007). Nat. Rev. Immunol, 7(6):429-42.
19. Goldring MB (2000). Osteoarthritis and cartilage: the role of cytokines. Curr. Rheumatol. Rep, 2(6):459-65.
20. Molnar V, Matišić V, Kodvanj I, Bjelica R, Jelec Z, Hudetz D, et al (2021). Cytokines and chemokines involved in osteoarthritis pathogenesis. Int. J. Mol. Sci, 22(17):9208.
21. Kass A, Hollan I, Fagerland MW, Gulseth HC, Torjesen PA, Førre Ø T (2015). Rapid Anti-Inflammatory Effects of Gonadotropin-Releasing Hormone Antagonism in Rheumatoid Arthritis Patients with High Gonadotropin Levels in the AGRA Trial. PLoS One,10(10):e0139439.
22. Okubo M, Kimura T, Fujita Y, Mochizuki S, Niki Y, Enomoto H, et al (2011). Semaphorin 3A is expressed in human osteoarthritic cartilage and antagonizes vascular endothelial growth factor 165–promoted chondrocyte migration: An implication for chondrocyte cloning. Arthritis & Rheumatism, 63(10):3000-9.
23. Sumi C, Hirose N, Yanoshita M, Takano M, Nishiyama S, Okamoto Y, et al (2018). Semaphorin 3A inhibits inflammation in chondrocytes under excessive mechanical stress. Mediators Inflamm, 2018.
24. Li Y, Xiao W, Luo W, Zeng C, Deng Z, Ren W, et al (2016). Alterations of amino acid metabolism in osteoarthritis: its implications for nutrition and health. Amino acids, 48(4):907-14.
25. Wen Z-H, Chang Y-C, Jean Y-H (2015). Excitatory amino acid glutamate: role in peripheral nociceptive transduction and inflammation in experimental and clinical osteoarthritis. Osteoarthr. Cartil, 23(11):2009-16.
26. Chen R, Han S, Liu X, Wang K, Zhou Y, Yang C, et al (2018). Perturbations in amino acids and metabolic pathways in osteoarthritis patients determined by targeted metabolomics analysis. J. Chromatogr. B, 1085:54-62.
27. Roseti L, Desando G, Cavallo C, Petretta M, Grigolo B (2019). Articular cartilage regeneration in osteoarthritis. Cells, 8(11):1305.
28. Hunter DJ, March L, Chew M (2020). Osteoarthritis in 2020 and beyond: a Lancet Commission. Lancet, 396(10264):1711-2.
29. Lv M, Zhou Y, Chen X, Han L, Wang L, Lu XL (2018). Calcium signaling of in situ chondrocytes in articular cartilage under compressive loading: Roles of calcium sources and cell membrane ion channels. J. Orthop. Res, 36(2):730-8.
30. Pingguan‐Murphy B, El‐Azzeh M, Bader D, Knight M (2006). Cyclic compression of chondrocytes modulates a purinergic calcium signalling pathway in a strain rate‐and frequency‐dependent manner. J. Cell. Physiol ,209(2):389-97.
31. Fields JK, Günther S, Sundberg EJ (2019). Structural basis of IL-1 family cytokine signaling. Front. immunol, 10:1412.
32. Attur M, Statnikov A, Samuels J, Li Z, Alekseyenko A, Greenberg J, et al (2015). Plasma levels of interleukin-1 receptor antagonist (IL1Ra) predict radiographic progression of symptomatic knee osteoarthritis. Osteoarthr. Cartil, 23(11):1915-24.
33. Wang X, Li F, Fan C, Wang C, Ruan H (2011). Effects and relationship of ERK1 and ERK2 in interleukin-1β-induced alterations in MMP3, MMP13, type II collagen and aggrecan expression in human chondrocytes. Int. J. Mol. Med, 27(4):583-9.
34. Jenei-Lanzl Z, Meurer A, Zaucke F (2019). Interleukin-1β signaling in osteoarthritis–chondrocytes in focus. Cell. Signal, 53:212-23.
35. Chow YY, Chin K-Y (2020). The role of inflammation in the pathogenesis of osteoarthritis. Mediators Inflamm, 2020.
36. Guo X, Xu T, Zheng J, Cui X, Li M, Wang K, et al (2020). Accumulation of synovial fluid CD19+ CD24hiCD27+ B cells was associated with bone destruction in rheumatoid arthritis. Sci. Rep, 10(1):1-10.
37. Tedder TF (2009). CD19: a promising B cell target for rheumatoid arthritis. Nat. Rev. Rheumatol, 5(10):572-7.
38. Vinatier C, Domínguez E, Guicheux J, Caramés B (2018). Role of the inflammation-autophagy-senescence integrative network in osteoarthritis. Front. physiol, 9:706.
39. Rahmati M, Nalesso G, Mobasheri A, Mozafari M (2017). Aging and osteoarthritis: central role of the extracellular matrix. ARR, 40:20-30.
40. Poulsen RC, Hearn JI, Dalbeth N (2021). The circadian clock: a central mediator of cartilage maintenance and osteoarthritis development?. Rheumatology, 60(7):3048-57.
41. Li J, Huang J, Dai L, Yu D, Chen Q, Zhang X, et al (2012). miR-146a, an IL-1β responsive miRNA, induces vascular endothelial growth factor and chondrocyte apoptosis by targeting Smad4. Arthritis research & therapy, 14(2):1-13.
42. Xu J, Qian X, Ding R (2021). MiR-24-3p attenuates IL-1β-induced chondrocyte injury associated with osteoarthritis by targeting BCL2L12. J. Orthop. Surg. Res, 16(1):1-10.
43. Kopańska M, Szala D, Czech J, Gabło N, Gargasz K, Trzeciak M, et al (2017). MiRNA expression in the cartilage of patients with osteoarthritis. J. Orthop. Surg. Res h, 12(1):1-7.
44. Zhang W, Hu C, Zhang C, Luo C, Zhong B, Yu X (2021). MiRNA-132 regulates the development of osteoarthritis in correlation with the modulation of PTEN/PI3K/AKT signaling. BMC Geriatr, 21(1):1-10.
45. Akhtar N, Rasheed Z, Ramamurthy S, Anbazhagan AN, Voss FR, Haqqi TM (2010). MicroRNA‐27b regulates the expression of matrix metalloproteinase 13 in human osteoarthritis chondrocytes. Arthritis & Rheumatism, 62(5):1361-71.
46. Philipot D, Guérit D, Platano D, Chuchana P, Olivotto E, Espinoza F, et al (2014). p16INK4a and its regulator miR-24 link senescence and chondrocyte terminal differentiation-associated matrix remodeling in osteoarthritis. Arthritis Res Ther, 16(1):1-12.
47. Song J, Jin E, Kim D, Kim K, Chun C, Jin E (2015). MicroRNA-222 regulates MMP-13 via targeting HDAC-4 during osteoarthritis pathogenesis. BBA Clin, 3: 79–89.
48. Song J, Kim D, Chun CH, Jin EJ (2015). Mi R‐370 and mi R‐373 regulate the pathogenesis of osteoarthritis by modulating one‐carbon metabolism via SHMT‐2 and MECP‐2, respectively. Aging cell, 14(5):826-37.
49. Song J, Kim D, Lee CH, Lee MS, Chun C-H, Jin E-J (2013). MicroRNA-488 regulates zinc transporter SLC39A8/ZIP8 during pathogenesis of osteoarthritis. J. Biomed. Sci, 20(1):1-6.
50. Withrow J, Murphy C, Dukes A, Fulzele S, Liu Y, Hunter M, et al (2016), editors. Synovial fluid exosomal MicroRNA profiling of osteoarthritis patients and identification of synoviocyte-chondrocyte communication pathway. ORS 2016 Annual Meeting.
2. Goldring MB (2012). Articular cartilage degradation in osteoarthritis. SAGE Publications Sage CA: Los Angeles, CA, 8(1): 7–9.
3. Sandell LJ (2012). Etiology of osteoarthritis: genetics and synovial joint development. Nat. Rev. Rheumatol, 8(2):77-89.
4. Chen D, Shen J, Zhao W, Wang T, Han L, Hamilton JL, et al (2017). Osteoarthritis: toward a comprehensive understanding of pathological mechanism. Bone Res,5(1):1-13.
5. Lotz M, Loeser RF (2012). Effects of aging on articular cartilage homeostasis. Bone, 51(2):241-8.
6. Chang L, Liu A, Xu J, Xu X, Dai J, Wu R, et al (2021). TDP-43 maintains chondrocyte homeostasis and alleviates cartilage degradation in osteoarthritis. Osteoarthr. Cartil,29(7):1036-47.
7. Polyakova J, Zavodovsky B, Seewordova L, Akhverdyan Y, Zborovskaya I (2015). THU0476 Pathogenic Relationship Between Osteoarthritis, Overweight and Inflammation. BMJ Publishing Group Ltd, 74(2).
8. Bos SD, Slagboom PE, Meulenbelt I (2008). New insights into osteoarthritis: early developmental features of an ageing-related disease. Curr Opin Rheumatol, 20(5):553-9.
9. Kang Y-J, Yoo J-I, Baek K-W. Differential gene expression profile by RNA sequencing study of elderly osteoporotic hip fracture patients with sarcopenia (2021). J. Orthop. Translat, 29:10-8.
10. Malakootian M, Gholipour A, Bagheri Moghaddam M, Arabian M, Oveisee M (2022). Potential roles of circular rnas and environmental and clinical factors in intervertebral disc degeneration. Environ. Health Eng. Manag, 9(2):189-200.
11. Chang L, Yao H, Yao Z, Ho KK-W, Ong MT-Y, Dai B, et al (2021). Comprehensive analysis of key genes, signaling pathways and miRNAs in human knee osteoarthritis: based on bioinformatics. Front. pharmacol,2237.
12. Ramos YF, den Hollander W, Bovée JV, Bomer N, van der Breggen R, Lakenberg N, et al (2014). Genes involved in the osteoarthritis process identified through genome wide expression analysis in articular cartilage; the RAAK study. PloS one, 9(7):e103056.
13. Malakootian M, Soveizi M, Gholipour A, Oveisee M (2023).Pathophysiology, Diagnosis, Treatment, and Genetics of Carpal Tunnel Syndrome: A Review. Cell. Mol. Neurobiol, 43(5):1817-1831.
14. Cui S, Zhang X, Hai S, Lu H, Chen Y, Li C, et al (2015). Molecular mechanisms of osteoarthritis using gene microarrays. Acta histochemica, 117(1):62-8.
15. Feng Z, Lian K (2015). Identification of genes and pathways associated with osteoarthritis by bioinformatics analyses. Eur Rev Med Pharmacol Sci, 19(5):736-44.
16. Zhen G, Wen C, Jia X, Li Y, Crane JL, Mears SC, et al (2013). Inhibition of TGF–β signaling in subchondral bone mesenchymal stem cells attenuates osteoarthritis. Nat. Med, 19(6):704.
17. Van Der Kraan PM (2017). The changing role of TGFβ in healthy, ageing and osteoarthritic joints. Nat. Rev. Rheumatol, 13(3):155-63.
18. McInnes IB, Schett G. Cytokines in the pathogenesis of rheumatoid arthritis (2007). Nat. Rev. Immunol, 7(6):429-42.
19. Goldring MB (2000). Osteoarthritis and cartilage: the role of cytokines. Curr. Rheumatol. Rep, 2(6):459-65.
20. Molnar V, Matišić V, Kodvanj I, Bjelica R, Jelec Z, Hudetz D, et al (2021). Cytokines and chemokines involved in osteoarthritis pathogenesis. Int. J. Mol. Sci, 22(17):9208.
21. Kass A, Hollan I, Fagerland MW, Gulseth HC, Torjesen PA, Førre Ø T (2015). Rapid Anti-Inflammatory Effects of Gonadotropin-Releasing Hormone Antagonism in Rheumatoid Arthritis Patients with High Gonadotropin Levels in the AGRA Trial. PLoS One,10(10):e0139439.
22. Okubo M, Kimura T, Fujita Y, Mochizuki S, Niki Y, Enomoto H, et al (2011). Semaphorin 3A is expressed in human osteoarthritic cartilage and antagonizes vascular endothelial growth factor 165–promoted chondrocyte migration: An implication for chondrocyte cloning. Arthritis & Rheumatism, 63(10):3000-9.
23. Sumi C, Hirose N, Yanoshita M, Takano M, Nishiyama S, Okamoto Y, et al (2018). Semaphorin 3A inhibits inflammation in chondrocytes under excessive mechanical stress. Mediators Inflamm, 2018.
24. Li Y, Xiao W, Luo W, Zeng C, Deng Z, Ren W, et al (2016). Alterations of amino acid metabolism in osteoarthritis: its implications for nutrition and health. Amino acids, 48(4):907-14.
25. Wen Z-H, Chang Y-C, Jean Y-H (2015). Excitatory amino acid glutamate: role in peripheral nociceptive transduction and inflammation in experimental and clinical osteoarthritis. Osteoarthr. Cartil, 23(11):2009-16.
26. Chen R, Han S, Liu X, Wang K, Zhou Y, Yang C, et al (2018). Perturbations in amino acids and metabolic pathways in osteoarthritis patients determined by targeted metabolomics analysis. J. Chromatogr. B, 1085:54-62.
27. Roseti L, Desando G, Cavallo C, Petretta M, Grigolo B (2019). Articular cartilage regeneration in osteoarthritis. Cells, 8(11):1305.
28. Hunter DJ, March L, Chew M (2020). Osteoarthritis in 2020 and beyond: a Lancet Commission. Lancet, 396(10264):1711-2.
29. Lv M, Zhou Y, Chen X, Han L, Wang L, Lu XL (2018). Calcium signaling of in situ chondrocytes in articular cartilage under compressive loading: Roles of calcium sources and cell membrane ion channels. J. Orthop. Res, 36(2):730-8.
30. Pingguan‐Murphy B, El‐Azzeh M, Bader D, Knight M (2006). Cyclic compression of chondrocytes modulates a purinergic calcium signalling pathway in a strain rate‐and frequency‐dependent manner. J. Cell. Physiol ,209(2):389-97.
31. Fields JK, Günther S, Sundberg EJ (2019). Structural basis of IL-1 family cytokine signaling. Front. immunol, 10:1412.
32. Attur M, Statnikov A, Samuels J, Li Z, Alekseyenko A, Greenberg J, et al (2015). Plasma levels of interleukin-1 receptor antagonist (IL1Ra) predict radiographic progression of symptomatic knee osteoarthritis. Osteoarthr. Cartil, 23(11):1915-24.
33. Wang X, Li F, Fan C, Wang C, Ruan H (2011). Effects and relationship of ERK1 and ERK2 in interleukin-1β-induced alterations in MMP3, MMP13, type II collagen and aggrecan expression in human chondrocytes. Int. J. Mol. Med, 27(4):583-9.
34. Jenei-Lanzl Z, Meurer A, Zaucke F (2019). Interleukin-1β signaling in osteoarthritis–chondrocytes in focus. Cell. Signal, 53:212-23.
35. Chow YY, Chin K-Y (2020). The role of inflammation in the pathogenesis of osteoarthritis. Mediators Inflamm, 2020.
36. Guo X, Xu T, Zheng J, Cui X, Li M, Wang K, et al (2020). Accumulation of synovial fluid CD19+ CD24hiCD27+ B cells was associated with bone destruction in rheumatoid arthritis. Sci. Rep, 10(1):1-10.
37. Tedder TF (2009). CD19: a promising B cell target for rheumatoid arthritis. Nat. Rev. Rheumatol, 5(10):572-7.
38. Vinatier C, Domínguez E, Guicheux J, Caramés B (2018). Role of the inflammation-autophagy-senescence integrative network in osteoarthritis. Front. physiol, 9:706.
39. Rahmati M, Nalesso G, Mobasheri A, Mozafari M (2017). Aging and osteoarthritis: central role of the extracellular matrix. ARR, 40:20-30.
40. Poulsen RC, Hearn JI, Dalbeth N (2021). The circadian clock: a central mediator of cartilage maintenance and osteoarthritis development?. Rheumatology, 60(7):3048-57.
41. Li J, Huang J, Dai L, Yu D, Chen Q, Zhang X, et al (2012). miR-146a, an IL-1β responsive miRNA, induces vascular endothelial growth factor and chondrocyte apoptosis by targeting Smad4. Arthritis research & therapy, 14(2):1-13.
42. Xu J, Qian X, Ding R (2021). MiR-24-3p attenuates IL-1β-induced chondrocyte injury associated with osteoarthritis by targeting BCL2L12. J. Orthop. Surg. Res, 16(1):1-10.
43. Kopańska M, Szala D, Czech J, Gabło N, Gargasz K, Trzeciak M, et al (2017). MiRNA expression in the cartilage of patients with osteoarthritis. J. Orthop. Surg. Res h, 12(1):1-7.
44. Zhang W, Hu C, Zhang C, Luo C, Zhong B, Yu X (2021). MiRNA-132 regulates the development of osteoarthritis in correlation with the modulation of PTEN/PI3K/AKT signaling. BMC Geriatr, 21(1):1-10.
45. Akhtar N, Rasheed Z, Ramamurthy S, Anbazhagan AN, Voss FR, Haqqi TM (2010). MicroRNA‐27b regulates the expression of matrix metalloproteinase 13 in human osteoarthritis chondrocytes. Arthritis & Rheumatism, 62(5):1361-71.
46. Philipot D, Guérit D, Platano D, Chuchana P, Olivotto E, Espinoza F, et al (2014). p16INK4a and its regulator miR-24 link senescence and chondrocyte terminal differentiation-associated matrix remodeling in osteoarthritis. Arthritis Res Ther, 16(1):1-12.
47. Song J, Jin E, Kim D, Kim K, Chun C, Jin E (2015). MicroRNA-222 regulates MMP-13 via targeting HDAC-4 during osteoarthritis pathogenesis. BBA Clin, 3: 79–89.
48. Song J, Kim D, Chun CH, Jin EJ (2015). Mi R‐370 and mi R‐373 regulate the pathogenesis of osteoarthritis by modulating one‐carbon metabolism via SHMT‐2 and MECP‐2, respectively. Aging cell, 14(5):826-37.
49. Song J, Kim D, Lee CH, Lee MS, Chun C-H, Jin E-J (2013). MicroRNA-488 regulates zinc transporter SLC39A8/ZIP8 during pathogenesis of osteoarthritis. J. Biomed. Sci, 20(1):1-6.
50. Withrow J, Murphy C, Dukes A, Fulzele S, Liu Y, Hunter M, et al (2016), editors. Synovial fluid exosomal MicroRNA profiling of osteoarthritis patients and identification of synoviocyte-chondrocyte communication pathway. ORS 2016 Annual Meeting.
| Files | ||
| Issue | Vol 52 No 12 (2023) | |
| Section | Original Article(s) | |
| DOI | https://doi.org/10.18502/ijph.v52i12.14326 | |
| Keywords | ||
| Osteoarthritis IL-1B Protein CD19 CACNA1G Hub genes | ||
| Rights and permissions | |
|
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. |
How to Cite
1.
Malakootian M, Gholipour A, Oveisee M. CD19, ALDH18A1, and CACNA1G as Significant Hub Genes in End-Stage Osteoarthritis. Iran J Public Health. 2023;52(12):2651-2662.
