Innate immunity, bone and cartilage metabolism in children with developmental dislocation of the hip – pilot study

Objective. Search for the relationship between innate immunity and bone and cartilage metabolism in patients with developmental dislocation of the hip (DDH).

Material and methods The study included 27 patients with DDH who underwent reduction of the hip at pediatric orthopaedic department of the Federal State Budgetary Educational Institution of Higher Education «Privolzhsky Research Medical University» of the Ministry of Health of the Russian Federation. The patients aged 15.0 ± 1.7 months. The study enrolled the babies diagnosed with grades III, IV, V unilateral or bilateral DDH as classified by M.V. Volkov, 1978. Patients with hip dysplasia (grade I DDH) or congenital hip subluxation (grade II DDH) were excluded from the study. The control group consisted of 15 patients without musculoskeletal pathology. The mean patients' age was 24.0 ± 1.8 months. Peripheral blood monocytes, toll-like receptor (TLR2, TLR4, TLR5) expression, serum concentrations of fibroblast growth factors (FGF), vascular endothelial growth factor (VEGF), serum magnesium, type I, II collagen and aggrecan were measured in patients of major and control groups.

Results. DDH patients showed statistically significant differences in all the parameters measured except for the type 2 collagen with decrease in peripheral blood monocyte and increase in TLR2 and TLR5 expression, slight increase in the serum magnesium with decreased concentration of aggrecan and increased FGF level. There was a two-fold decrease in VEGF level and a two-fold increase in type I collagen concentration. There were moderate significant correlations for monocyte matches TLR2 and TLR2 – TLR5 in major group. Three main factors detected with factor analysis included (1) monocytes, TLR2 and TLR5 as most meaningful, (2) FGF and type 2 collagen and (3) aggrecan.

Conclusion. The findings suggested that specific factors of innate immunity can be involved in the pathogenesis of DDH. Toll receptors regulate many metabolic pathways and connective tissue metabolism, More studies are needed to further explore this topic.

1. Baindurashvili A.G., Voloshin S.Iu., Krasnov A.I. Vrozhdennyi vyvikh bedra u detei grudnogo vozrasta: klinika, diagnostika, konservativnoe lechenie [Congenital hip dislocation in infants: clinical picture, diagnosis, conservative treatment]. 2nd Ed. SPb., SpetsLit., 2016, 103 p. (in Russian)

2. Tvorogova T.M., Vorobeva A.S. Nedifferentsirovannaia displaziia soedinitelnoi tkani s pozitsii dizelementoza u detei i podrostkov [Non-differentiated connective tissue dysplasia from the position of diselementosis in children and adolescents]. Russkii Meditsinskii Zhurnal, 2012, vol. 20, no. 24, pp. 1215-1221. (in Russian)

3. Beliaeva E.L., Zemtsovskii E.V. Osobennosti patologii verkhnikh otdelov zheludochno-kishechnogo trakta u lits molodogo vozrasta s sindromom displazii soedinitelnoi tkani serdtsa [Characteristics of the pathology of the upper gastrointestinal tract in young people with dysplasia of the heart connective tissue]. Gastroenterologiia Sankt-Peterburga, 2005, no. 1-2, pp. 28-32. (in Russian)

4. Moskovich G.I., Dulkin L.A., Geniatulin R.U. Kliniko-morfologicheskie osobennosti sindroma razdrazhennogo kishechnika u detei na fone nedifferentsirovannoi soedinitelnotkannoi displazii [Clinical-and-morphological characteristics of the irritable bowel syndrome in children on the background of non-differentiated connective tissue dysplasia]. Voprosy Prakticheskoi Pediatrii, 2008, vol. 3, no. 1, pp.19-25. (in Russian)

5. Solyeykо O.V., Osypenko I.P., Galych T.V., Chernykh M.O. Assessment of rehabilitation potential in patients with vascular dysfunction caused by undifferentiated connective tissue dysplasia. Wiad. Lek., 2017, vol. 70, no. 2, pt. 2, pp. 282-285.

6. Arita M., Fertala J., Hou C., Kostas J., Steplewski A., Fertala A. Prospects and limitations of improving skeletal growth in a mouse model of spondyloepiphyseal dysplasia caused by R992C (p.R1192C) substitution in collagen II. PLoS One, 2017, vol. 12, no. 2, pp. e0172068. DOI: 10.1371/journal.pone.0172068

7. Khokhlova O.I., Kalaeva G.Iu., Ust'iantseva I.M. Characteristics of the bone tissue metabolism in adolescents with the connective tissue's undifferentiated dysplasia. Fiziol Cheloveka, 2014, vol. 40, no. 3, pp. 101-108. (in Russian)

8. Pearce E.L., Pearce E.J. Metabolic pathways in immune cell activation and quiescence. Immunity, 2013, vol. 38, no. 4, pp. 633-643. DOI: 10.1016/j.immuni.2013.04.005

9. Ganeshan K., Chawla A. Metabolic regulation of immune responses. Annu. Rev. Immunol., 2014, vol. 32, pp. 609-34. DOI: 10.1146/annurevimmunol-032713-120236

10. Villarino A.V., Kanno Y., O'Shea J.J. Mechanisms and consequences of Jak-STAT signaling in the immune system. Nat. Immunol., 2017, vol. 18, no. 4, pp. 374-384. DOI: 10.1038/ni.3691

11. Volkov M.V., Dedova V.D. Detskaia ortopediia [Pediatric Orthopaedics]. M., Meditsina, 1972, 240 p. (in Russian)

12. Zhang Z., Liu Q., Liu M., Wang H., Dong Y., Ji T., Liu X., Jiang Y., Cai L., Wu Y. Upregulation of HMGB1-TLR4 inflammatory pathway in focal cortical dysplasia type II. J. Neuroinflammation, 2018, vol. 15, no. 1, pp. 27. DOI: 10.1186/s12974-018-1078-8

13. Trotta T., Porro C., Calvello R., Panaro M.A. Biological role of Toll-like receptor-4 in the brain. J. Neuroimmunol., 2014, vol. 268, no. 1-2, pp. 1-12. DOI: 10.1016/j.jneuroim.2014.01.014

14. Koh J., Kurago Z.B. Expanded Expression of Toll-Like Receptor 2 in Proliferative Verrucous Leukoplakia. Head Neck Pathol., 2019, vol. 13, no. 4, pp. 635-642. DOI: 10.1007/s12105-019-01028-y

15. Kurago Z.B., Lam-ubol A., Stetsenko A., De La Mater C., Chen Y., Dawson D.V. Lipopolysaccharide-squamous cell carcinoma-monocyte interactions induce cancer-supporting factors leading to rapid STAT3 activation. Head Neck Pathol., 2008, vol. 2, no. 1, pp. 1-12. DOI: 10.1007/s12105-007-0038-x

16. Kawai T., Akira S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol., 2010, vol. 11, no. 5, pp. 373-384. DOI: 10.1038/ni.1863

17. Gibson B.G., Briggs M.D. The aggrecanopathies; an evolving phenotypic spectrum of human genetic skeletal diseases. Orphanet. J. Rare Dis., 2016, vol. 11, no. 1, pp. 86. DOI: 10.1186/s13023-016-0459-2

18. Tompson S.W., Merriman B., Funari V.A., Fresquet M., Lachman R.S., Rimoin D.L., Nelson S.F., Briggs M.D., Cohn D.H., Krakow D. A recessive skeletal dysplasia, SEMD aggrecan type, results from a missense mutation affecting the C-type lectin domain of aggrecan. Am. J. Hum. Genet., 2009, vol. 84, no. 1, pp. 72-79. DOI: 10.1016/j.ajhg.2008.12.001

19. Feng W.J., Wang H., Shen C., Zhu J.F., Chen X.D. Severe cartilage degeneration in patients with developmental dysplasia of the hip. IUBMB Life, 2017, vol. 69, no. 3, pp. 179-187. DOI: 10.1002/iub.1606

20. Shchelkunova E.I., Voropaeva A.A., Russova T.V., Baitov V.S. Sintez agrekana i kollagena II tipa in vitro khondrotsitami iz raznykh zon kolennogo sustava bolnykh gonartrozom [Synthesis of aggrecan and type II collagen in vitro by chondrocytes from different zones of the knee of patients with gonarthrosis]. Sovremennye Problemy Nauki i Obrazovaniia, 2016, no. 6, pp. 1-10. (in Russian)

21. Olsen S.K., Garbi M., Zampieri N., Eliseenkova A.V., Ornitz D.M., Goldfarb M., Mohammadi M. Fibroblast growth factor (FGF) homologous factors share structural but not functional homology with FGFs. J. Biol. Chem., 2003, vol. 278, no. 36, pp. 34226-34236. DOI: 10.1074/jbc.M303183200

22. Itoh N., Ornitz D.M. Evolution of the Fgf and Fgfr gene families. Trends Genet., 2004, vol. 20, no. 11, pp. 563-569. DOI: 10.1016/j.tig.2004.08.007

23. Ferrara N., Gerber H.P., LeCouter J. The biology of VEGF and its receptors. Nat. Med., 2003, vol. 9, no. 6, pp. 669-676. DOI: 10.1038/nm0603-669

24. Monk B.J., Willmott L.J., Sumner D.A. Anti-angiogenesis agents in metastatic or recurrent cervical cancer. Gynecol. Oncol., 2010, vol. 116, no. 2, pp. 181-186. DOI: 10.1016/j.ygyno.2009.09.033

25. Rotar I.C., Dumitras D.E., Popp R.A., Petrisor F.M., Cotutiu P., Stamatian F., Muresan D. VEGF +936 C/T Genetic Polymorphism in Patients with Cervical Dysplasia. Anal. Cell. Pathol. (Amst), 2016, vol. 2016, pp. 6074275. DOI: 10.1155/2016/6074275

26. Zhao X.M., Wang E.B., Li J.J., Zhou C.F., Zhao Q., Zhang L.J. [Developmental changes of acetabular cartilage complex: an experimental study of a straight-leg swaddle model of newborn rats]. Zhongguo Dang Dai Er Ke Za Zhi, 2009, vol. 11, no. 10, pp. 836-840. (in Chinese)

27. Alekseeva L.I., Zaitseva E.M. Klinicheskie podkhody k lecheniiu osteoartroza [Clinical approaches to osteoarthrosis treatment]. Russkii Meditsinskii Zhurnal, 2006, vol. 14, no. 6, pp. 450-453. (in Russian)

28. Badokin V.V. Puti optimizatsii terapii osteoartroza [Ways of osteoarthrosis optimization]. Russkii Meditsinskii Zhurnal, 2006, vol. 14, no. 25, pp. 1824-1828. (in Russian)