Matrix metalloproteinases in children with uncomplicated compression fractures of the spine

The aim of the study was to determine changes in the content of matrix metalloproteinases (MMP) and their tissue inhibitor in children with uncomplicated compression fractures of the spine (UCFS).

Materials and methods. Eighty-five children, including 69 patients with UCFS (average age 12.3 ± 2.6 years), were comprehensively examined. The reference group consisted of 16 children (average age 11.8 ± 2.7 years) without spinal pathology. During the diagnostic period for 1–3 days, changes in the MMP content and their tissue inhibitor (TIMP-1) in blood serum were determined by the enzyme immunoassay method in all children after trauma.

Results. It was found that in the acute period after spinal injury, the blood levels of gelatinases (MMP-2 and ММР-9), stromelysin (MMP-3), and collagenases (MMP-8) significantly increased compared to their levels in children of the reference group. At the same time, the levels of TIMP-1 and the ratio of MMP/TIMP-1 concentrations in the blood of patients with UCFS significantly decreased compared to the control, which indicates the predominance of the proteolytic effect of MMP. Analysis of changes in the content of MMP in the blood in UCFS boys and girls did not reveal significant differences in the levels of the studied MMP and TIMP-1, except for a significant increase in the concentrations of stromelysin (MMP-3) in the blood serum of boys compared with its level in girls and the control. With different severity of the course of UCFS in children, a significant increase in MMP concentrations associated with an increase in the severity of the injury was revealed, and a substantial decrease in the content of TIMP-1 in the blood of patients compared to its levels in children with 1–2 degrees of severity and control.

Conclusion. The established patterns indicate that the determination of the content of MMR and TIMP-1 in the blood in UCFS children allows monitoring the course of the reparative process after injury to the vertebral bodies in children.

Contribution:
Smirnov I.Е., Каraseva О.V., Кucherenko А.G. — concept and design of the study;
Каraseva О.V., Pоrоkhina Е.А., Sarukhanyan О.О. — collection of material;
Кucherenko А.G., Smirnov I.Е. — statistical processing;
Smirnov I.Е. — writing of the text;
Fisenko A.P., Mitish V.A. — editing.
All co-authors — approval of the final version of the article, responsibility for the integrity of all parts of the article.

Informed consent: written voluntary informed consent to participate in the study was obtained from the parents of the patients.

Acknowledgment. The study had no sponsorship.

Conflict of interest. The authors declare that there is no conflict of interest.

Received: April 21, 2021
Accepted: April 22, 2021
Published: May 14, 2021

1. Mäyränpää M.K., Viljakainen H.T., Toiviainen-Salo S., Kallio P.E., Mäkitie O. Impaired bone health and asymptomatic vertebral compressions in fracture-prone children: a case-control study. J Bone Miner Res. 2012; 27(6): 1413-24. https://doi.org/10.1002/jbmr.1579

2. Huisman T.A., Poretti A. Trauma. Handb Clin Neurol. 2016;136:1199-220. https://doi.org/10.1016/B978-0-444-53486-6.00062-4

3. Sorokovikov V.A., Stemplevskiy O.P., Byankin V.F., Alekseeva N.V. Clinical features, diagnosis and treatment of spinal injuries in children. Acta biomedica scientifica. 2018; 3(2): 68-74. (In Russian). https://doi.org/10.29413/ABS.2018-3.2.12

4. Mikrogianakis A., Grant V. The Kids Are Alright: Pediatric Trauma Pearls. Emerg Med Clin North Am. 2018; 36(1): 237-57. https://doi.org/10.1016/j.emc.2017.08.015

5. Traylor K.S., Kralik S.F., Radhakrishnan R. Pediatric Spine Emergencies. Semin Ultrasound CT MR. 2018; 39(6): 605-17. https://doi.org/10.1053/j.sult.2018.09.002

6. Khusainov N.O., Vissarionov S.V. Compression fractures of the spine in children: isn’t it time to change something? Khirurgiya pozvonochnika.2019; 16(4): 6-12. https://doi.org/10.14531/ss2019.4.6-12

7. Merkulov V.N., Bychkova V.S., Mininkov D.S. Modern approach to the diagnosis of compression fractures of the vertebral bodies in children and adolescents. Detskaya khirurgiya. 2012; 4: 49-51. (In Russian)

8. Skryabin E.G., Smirnykh A.G., Bukseev A.N., Akselrov M.A., Naumov S.V., Sidorenko A.V., et al. Multiple fractures of vertebral bodies in children and adolescents. Polytrauma. 2020;3:45-53.(In Russian) https://doi.org/10.24411/1819-1495-2020-10032

9. Weiß T., Disch A.C., Kreinest M., Jarvers J.S., Herren C., Jung M.K., et al. Diagnostics and treatment of thoracic and lumbar spine trauma in pediatric patients: Recommendations from the Pediatric Spinal Trauma Group. Unfallchirurg. 2020; 123(4): 269-79. https://doi.org/10.1007/s00113-020-00790-x

10. Krokhina K.N., Smirnov I.E., Belyaeva I.A. Features of bone formation in newborns. Rossiyskiy pediatricheskiy zhurnal. 2010; 5: 36-41. (In Russian)

11. Vaněk P., Kaiser R., Saur K., Beneš V. History, development and use of classification of thoracolumbar spine fractures. Rozhl Chir. 2020; 99(1): 15-21. https://doi.org/10.33699/PIS.2020.99.1.15-21

12. Daniels A.H., Sobel A.D., Eberson C.P. Pediatric thoracolumbar spine trauma. J Am Acad Orthop Surg. 2013; 21(12): 707-16. https://doi.org/10.5435/JAAOS-21-12-707

13. Hardy E., Fernandez-Patron C. Destroy to Rebuild: The Connection Between Bone Tissue Remodeling and Matrix Metalloproteinases. Front Physiol. 2020; 11: 47. https://doi.org/10.3389/fphys.2020.00047

14. Hussein A.I., Mancini C., Lybrand K.E., Cooke M.E., Matheny H.E., Hogue B.L., et al. Serum proteomic assessment of the progression of fracture healing. J Orthop Res. 2018; 36(4): 1153-63. https://doi.org/10.1002/jor.23754

15. Azevedo A., Prado A.F., Feldman S., de Figueiredo F.A.T., Dos Santos M.C.G., Issa J.P.M. MMPs are Involved in Osteoporosis and are Correlated with Cardiovascular Diseases. Curr Pharm Des. 2018; 24(16): 1801-10. https://doi.org/10.2174/1381612824666180604112925

16. Smirnov I.E., Roshal L.M., Kucherenko A.G., Karaseva O.V., Ponina I.V. Changes in the blood serum content of bone biomarkers and cytokines in children with combined trauma. Rossiyskiy pediatricheskiy zhurnal. 2017; 20(6): 371-8. (in Russian) https://doi.org/10.18821/1560-9561-2017-20-6-371-378

17. Wigner N.A., Kulkarni N., Yakavonis M., Young M., Tinsley B., Meeks B. et al. Urine matrix metalloproteinases (MMPs) as biomarkers for the progression of fracture healing. Injury. 2012; 43(3): 274-8. https://doi.org/10.1016/j.injury.2011.05.038

18. Vilaca T., Gossiel F., Eastell R. Bone Turnover Markers: Use in Fracture Prediction. J Clin Densitom. 2017; 20(3): 346-52. https://doi.org/10.1016/j.jocd.2017.06.020

19. Oh T., Naka T. Comparison of bone metabolism based on the different ages and competition levels of junior and high school female rhythmic gymnasts. J Exerc Nutrition Biochem. 2017; 21(2): 9-15.

20. Liu C., Cui X., Ackermann T.M., Flamini V., Chen W., Castillo A.B. Osteoblast-derived paracrine factors regulate angiogenesis in response to mechanical stimulation. Integr Biol (Camb). 2016; 8(7): 785-94.

21. Franceschi R.T., Ge C. Control of the Osteoblast Lineage by Mitogen-Activated Protein Kinase Signaling. Curr Mol Biol Rep. 2017; 3(2): 122-32.

22. Yang S.Y., Strong N., Gong X., Heggeness M.H. Differentiation of nerve-derived adult pluripotent stem cells into osteoblastic and endothelial cells. Spine J. 2017; 17(2): 277-81.

23. Bode W., Maskos K. Structural basis of the matrix metalloproteinases and their physiological inhibitors, the tissue inhibitors of metalloproteinases. Biol Chem. 2003; 384(6): 863-72. https://doi.org/10.1515/BC.2003.097

24. Nagase H., Visse R., Murphy G. Structure and function of matrix metalloproteinases and TIMPs. Cardiovasc Res. 2006; 69(3): 562-73. https://doi.org/10.1016/j.cardiores.2005.12.002

25. Panwar P., Butler G.S., Jamroz A., Azizi P., Overall C.M., Brömme D. Aging-associated modifications of collagen affect its degradation by matrix metalloproteinases. Matrix Biol. 2017. pii: S0945-053X(17)30130-0. https://doi.org/10.1016/j.matbio.2017.06.004

26. Movilla N., Borau C., Valero C., García-Aznar J.M. Degradation of extracellular matrix regulates osteoblast migration: A microfluidic-based study. Bone. 2017; 107(1): 10-7.

27. Paiva K.B.S., Granjeiro J.M. Matrix Metalloproteinases in Bone Resorption, Remodeling, and Repair. Prog Mol Biol Transl Sci. 2017; 148: 203-303. https://doi.org/10.1016/bs.pmbts.2017.05.001

28. Van den Steen P.E., Dubois B., Nelissen I., Rudd P.M., Dwek R.A., Opdenakker G. Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9).Crit Rev Biochem Mol Biol. 2002; 37(6): 375-536. https://doi.org/10.1080/10409230290771546

29. Vandooren J., Van den Steen P.E., Opdenakker G. Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9): the next decade. Crit Rev Biochem Mol Biol. 2013; 48(3): 222-72. https://doi.org/10.3109/10409238.2013.770819

30. Visse R., Nagase H. Matrix metalloproteinases and tissue inhibitors of metalloproteinases: structure, function, and biochemistry. Circ Res. 2003; 92(8): 827-39. https://doi.org/10.1161/01.RES.0000070112.80711.3D

31. Crane JL, Xian L, Cao X. Role of TGF-β Signaling in Coupling Bone Remodeling. Methods Mol Biol. 2016; 1344: 287-300. https://doi.org/10.1007/978-1-4939-2966-5_18

32. Crane J.L., Cao X. Bone marrow mesenchymal stem cells and TGF-β signaling in bone remodeling. J Clin Invest. 2014; 124(2): 466-72. https://doi.org/10.1172/JCI70050

33. Liao H.T., Chen C.T. Osteogenic potential: Comparison between bone marrow and adipose-derived mesenchymal stem cells. World J Stem Cells. 2014; 6(3): 288-95.

34. Hussein A.I., Mancini C., Lybrand K.E., Cooke M.E., Matheny H.E., Hogue B.L. et al. Serum proteomic assessment of the progression of fracture healing. J Orthop Res. 2018; 36(4): 1153-63. https://doi.org/10.1002/jor.23754

35. Wang T., Zhang X., Bikle D.D. Osteogenic Differentiation of Periosteal Cells During Fracture Healing. J Cell Physiol. 2017; 232(5): 913-21. https://doi.org/10.1002/jcp.25641

36. Schnake K.J., Schroeder G.D., Vaccaro A.R., Oner C. AOSpine Classification Systems (Subaxial, Thoracolumbar). J Orthop Trauma. 2017; 31(Suppl 4): 14-23. https://doi.org/10.1097/BOT.0000000000000947

37. Baindurashvili A.G., Vissarionov S.V., Pavlov I.V., Kokushin D.N., Lein G.A. Conservative treatment of children with vertebral compression fractures of the thoracic and lumbar spine in the Russian Federation. Оrtopediya,travmatologiya i vosstanovitelnaya khirurgiya detskogo vozrasta. 2016; 4(1): 48-56.(In Russian). https://doi.org/10.17816/ptors4148-56

38. Spiegl U.J., Fischer K., Schmidt J., Schnoor J., Delank S., Josten C., et al. The Conservative Treatment of Traumatic Thoracolumbar Vertebral Fractures. Dtsch Arztebl Int. 2018; 115(42): 697-704. https://doi.org/10.3238/arztebl.2018.0697

39. Kyriakou A., Shepherd S., Mason A., S Faisal A. Prevalence of Vertebral Fractures in Children with Suspected Osteoporosis. J Pediatr. 2016; 179: 219-25. https://doi.org/10.1016/j.jpeds.2016.08.075

40. Grover M., Bachrach L.K. Osteoporosis in Children with Chronic Illnesses: Diagnosis, Monitoring, and Treatment. Curr Osteoporos Rep.2017; 15(4): 271-82. https://doi.org/10.1007/s11914-017-0371-2

41. Yuasa M., Saito M., Molina C., Moore-Lotridge S.N., Benvenuti M.A., Mignemi N.A., et al. Unexpected timely fracture union in matrix metalloproteinase 9 deficient mice. PLoS One. 2018;13(5):e0198088. https://doi.org/10.1371/journal.pone.0198088

42. Tamminen I.S., Mäyränpää M.K., Turunen M.J., Isaksson H, Mäkitie O., Jurvelin J.S. et al. Altered bone composition in children with vertebral fracture. J Bone Miner Res. 2011; 26(9): 2226-34. https://doi.org/10.1002/jbmr.409

43. Garcia I., Chiodo V., Ma Y., Boskey A. Evidence of altered matrix composition in iliac crest biopsies from patients with idiopathic juvenile osteoporosis. Connect Tissue Res. 2016; 57(1): 28-37. https://doi.org/10.3109/03008207.2015.1088531

44. Adler D., Jarvers J.S., Tschoeke S.K., Siekmann H. Posttraumatic vertebral disc alterations after B and C type spinal injuries in childhood-Clinical and radiological 10-year results for two cases.Unfallchirurg. 2020; 123(4): 302-8. https://doi.org/10.1007/s00113-020-00780-z

45. Teleshov N.V., Sarukhanyan O.O. Uncomplicated trauma of the vertebral bodies in children. Meditsinskiy alfavit. 2014; 9: 42-7. (In Russian)

46. Alqahtani F.F., Offiah A.C. Diagnosis of osteoporotic vertebral fractures in children. Pediatr Radiol. 2019; 49(3): 283-96. https://doi.org/10.1007/s00247-018-4279-5

47. Xu W.L., Zhao Y. Comprehensive analysis of lumbar disc degeneration and autophagy-related candidate genes, pathways, and targeting drugs. J Orthop Surg Res. 2021; 16(1): 252. https://doi.org/10.1186/s13018-021-02417-2

48. Hsu H.T., Yue C.T., Teng M.S., Tzeng I.S., Li T.C., Tai P.A., et al. Immunohistochemical score of matrix metalloproteinase-1 may indicate the severity of symptomatic cervical and lumbar disc degeneration. Spine J. 2020; 20(1): 124-37. https://doi.org/10.1016/j.spinee.2019.08.004

49. Wang Y., Dai G., Jiang L., Liao S., Xia J. Microarray analysis reveals an inflammatory transcriptomic signature in peripheral blood for sciatica. BMC Neurol. 2021; 21(1): 50. https://doi.org/10.1186/s12883-021-02078-y

50. Arpino V., Brock M., Gill S.E. The role of TIMPs in regulation of extracellular matrix proteolysis. Matrix Biol. 2015; 44-46: 247–54. https://doi.org/10.1016/j.matbio.2015.03.005

51. Ardi V.C., Kupriyanova T.A., Deryugina E.I., Quigley J.P. Human neutrophils uniquely release TIMP-free MMP-9 to provide a potent catalytic stimulator of angiogenesis. Proc Natl Acad Sci USA. 2007; 104(51): 20262-7. https://doi.org/10.1073/pnas.0706438104

52. Zhang J.F., Wang G.L., Zhou Z.J., Fang X.Q., Chen S., Fan S.W. Expression of Matrix Metalloproteinases, Tissue Inhibitors of Metalloproteinases, and Interleukins in Vertebral Cartilage Endplate. Orthop Surg. 2018; 10(4): 306-11. https://doi.org/10.1111/os.12409

53. Li H.R., Cui Q., Dong Z.Y., Zhang J.H., Li H.Q., Zhao L. Downregulation of miR-27b is Involved in Loss of Type II Collagen by Directly Targeting Matrix Metalloproteinase 13 (MMP13) in Human Intervertebral Disc Degeneration. Spine (Phila Pa 1976). 2016; 41(3): 116-23. https://doi.org/10.1097/BRS.0000000000001139

54. Stevens D.A., Hasserjian R.P., Robson H., Siebler T., Shalet S.M., Williams G.R. Thyroid hormones regulate hypertrophic chondrocyte differentiation and expression of parathyroid hormone-related peptide and its receptor during endochondral bone formation. J Bone Miner Res. 2000; 15(12): 2431-42. https://doi.org/10.1359/jbmr.2000.15.12.2431

55. Limmer A., Wirtz D.C. Osteoimmunology: Influence of the Immune System on Bone Regeneration and Consumption. Z Orthop Unfall. 2017; 155(3): 273-80.

56. Bigham-Sadegh A., Oryan A. Basic concepts regarding fracture healing and the current options and future directions in managing bone fractures. Int Wound J. 2015; 12(3): 238-47. https://doi.org/10.1111/iwj.12231

57. Wahl E.P., Lampley A.J., Chen A., Adams S.B., Nettles D.L., Richard M.J. Inflammatory cytokines and matrix metalloproteinases in the synovial fluid after intra-articular elbow fracture. J Shoulder Elbow Surg. 2020; 29(4): 736-42. https://doi.org/10.1016/j.jse.2019.09.024