Vol 95, No 2 (2024)
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Osteopontin as a marker of endometriosis — the current state of knowledge

Joanna Figula1, Rafal M. Baran2, Robert Jach1
Pubmed: 37743647
Ginekol Pol 2024;95(2):152-155.

Abstract

Endometriosis is a disease affecting mainly women of childbearing age, where ectopic endometrial lesions occur outside the uterine cavity. Its main symptoms are chronic pain, infertility and dysmenorrhea. These symptoms significantly reduce the quality of life of patients suffering from this disease. Despite advanced research, the exact etiopathogenesis of endometriosis is still unknown and various theories explaining its origin are postulated in the course of research.

Osteopontin is a protein originally discovered in the bone matrix and then in various tissues and organs of the body such as the kidneys, lungs, reproductive organs, vascular epithelial cells or some cancer cells. It is involved in processes such as cell adhesion and migration, angiogenesis and the promotion of tumor cell metastasis.

These processes play a role in the pathogenesis of endometriosis, hence intensive research on the role of osteopontin in the development of this disease is an interesting research direction.

ORIGINAL PAPER/OBSTETRICS

Ginekologia Polska

2024, vol. 95, no. 2, 152–155

Copyright © 2024 PTGiP

ISSN 0017–0011, e-ISSN 2543–6767

DOI 10.5603/gpl.86232

Osteopontin as a marker of endometriosis — the current state of knowledge

Joanna Figula1Rafal M. Baran2Robert Jach1
1Collegium Medicum, Jagiellonian University, Cracow, Poland
2Clinical Department of Gynaecological Endocrinology and Gynaecology, University Hospital in Cracow, Poland

Corresponding author:

Rafal M. Baran

Clinical Department of Gynaecological Endocrinology and Gynaecology, University Hospital in Cracow, 23 Kopernika St., 31501 Cracow, Poland

e-mail: rabaran@su.krakow.pl

Received: 3.10.2021 Accepted: 9.11.2022 Early publication date: 19.09.2023

This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, allowing to download articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially.

ABSTRACT
Endometriosis is a disease affecting mainly women of childbearing age, where ectopic endometrial lesions occur outside the uterine cavity. Its main symptoms are chronic pain, infertility and dysmenorrhea. These symptoms significantly reduce the quality of life of patients suffering from this disease. Despite advanced research, the exact etiopathogenesis of endometriosis is still unknown and various theories explaining its origin are postulated in the course of research.
Osteopontin is a protein originally discovered in the bone matrix and then in various tissues and organs of the body such as the kidneys, lungs, reproductive organs, vascular epithelial cells or some cancer cells. It is involved in processes such as cell adhesion and migration, angiogenesis and the promotion of tumor cell metastasis.
These processes play a role in the pathogenesis of endometriosis, hence intensive research on the role of osteopontin in the development of this disease is an interesting research direction.
Keywords: endometriosis; osteopontin; gene expression; SPP1
Ginekologia Polska 2024; 95, 2: 152155

INTRODUCTION

Endometriosis

Endometriosis is a disease affecting women of reproductive age, manifested by multiple symptoms, including chronic pelvic pain, menstrual cycle disorders, dyspareunia (painful intercourse) and fertility problems [1]. It involves the presence of active endometrial tissue outside the uterine cavity. Most often, these lesions are located in the ovaries, pouch of Douglas, uterine ligaments and the peritoneum of the small pelvis, but there are also rare locations, such as lungs or lymph nodes, or a caesarean section scar [2].

Endometriosis is not only specific symptoms, but also a chronic disease with long-term consequences, such as infertility [3], adverse psychological effects for both the woman and her partner [4, 5], a decrease in the quality of life and high costs associated with diagnostics and treatment.

The exact incidence of endometriosis is unknown. It is estimated, that it affects 210% of women in the general population [6]. Endometriosis is diagnosed in approximately 33% of women suffering from chronic pelvic pain and in as many as 2050% of infertile women [7, 8].

Currently, one of the most commonly used classification of endometriosis is the revised Classification of Endometriosis of the American Society for Reproductive Medicine (rASRM) scale (Tab. 1, 2) [9]. It is a 4-stage scale that assesses the severity of endometriosis on the basis of the size of the foci, the depth of their infiltration and the presence of endometrial cysts and adhesions within the reproductive organ.

Table 1. Revised Classification of Endometriosis of the American Society for Reproductive Medicine [9]

Location

Endometriosis

Size of lesions

< 1 cm

1–3 cm

> 3 cm

Peritoneum

Superficial

1

2

4

Deep

2

4

6

Right ovary

Superficial

1

2

4

Deep

4

16

20

Left ovary

Superficial

1

2

4

Deep

4

16

20

Posterior Cul-de-sac obliteration

Partial

Complete

4

40

Adhesions

Degree of enclosure

< 1/3

1/3–2/3

> 2/3

Right ovary

Filmy

1

2

4

Dense

4

8

16

Left ovary

Filmy

1

2

4

Dense

4

8

16

Right fallopian tube

Filmy

1

2

4

Dense

4*

8*

16

Left fallopian tube

Filmy

1

2

4

Dense

4*

8*

16

*If the fimbriated end of the fallopian tube is completely enclosed, change the point assignment to 16

Table 2. Clinical advancement of endometriosis according to revised Classification of Endometriosis of the American Society for Reproductive Medicine (rASRM) [9]

Clinical advancement of endometriosis according to rASRM

Amount of points

I (Minimal)

15

II (Mild)

615

III (Moderate)

1640

IV (Severe)

> 40

Endometriosis is a disease in which symptoms significantly reduce the quality of life [10]. Chronic pelvic pain independent of the cycle day, painful menstruation (dysmenorrhea), pain during intercourse (dyspareunia), spotting after intercourse, pain during urination (dysuria) or pain during defecation (dyschezia), often with bleeding from the lower gastrointestinal tract are one of the most common symptoms of endometriosis [10]. A serious problem in patients suffering from endometriosis is reduced fertility or infertility [10]. Interestingly, there is no linear correlation between the severity of the disease and symptoms, additionally some patients remain asymptomatic [11]. However, there is a relationship between the location of endometrial foci and clinical symptoms. Deep infiltrating endometriosis (DIE) lesions located within the utero-rectal septum, sacrouterine ligaments and pouch of Douglas are mainly manifested as dyspareunia and dyschezia [12]. Endometriosis in the pelvic organs such as the large intestine, rectum, ureters or bladder may be responsible for symptoms such as dysuria, dyschezia, or even hematuria or bleeding from the lower gastrointestinal tract. Numerous implants in the pelvic peritoneum correlate with dysmenorrhea [12].

The etiopathogenesis of endometriosis is unknown; today there are several established theories attempting to explain the mechanism of the disease. These include: Sampson’s implantation theory [13], the theory of the spread of endometrial cells through the lymphatic and circulatory systems [14] or the Meyer’s theory of metaplasia [15]. Additionally, immunological and genetic factors as well as endometrial disorders related to the increased ability of endometrial stromal and epithelial cells to proliferate, which facilitate the survival of endometrial tissue outside the uterine cavity, are taken into account [16]. As can be seen from the above examples, the complexity of the process of the formation and spread of endometriosis, its numerous forms, the ability to evolve, dependence on locoregional conditions as well as on the immune and hormonal condition of the whole organism make the explanation of the etiopathogenesis of endometriosis extremely difficult and still not fully understood.

In the diagnostic process of endometriosis, the basic diagnostic tool used in clinical practice is a properly collected medical history. Symptoms such as dysmenorrhea, pain during intercourse, pelvic pain unrelated to the menstrual cycle and fertility disorders are characteristic of endometriosis. In the detection of endometriosis, diagnostic techniques are used, such as gynecological speculum examination combined with a bimanual examination and transvaginal or transrectal ultrasound examination. The gold standard used in diagnostics is laparoscopy [17].

The search for a highly sensitive and specific marker of endometriosis are going on for many years, but so far, no satisfactory results have been obtained in this direction. Currently, the main areas of interest in current research are the search for markers in plasma, urine, uterine fluid or menstrual blood [17]. The minimally invasive procedures also include the collection of pelvic fluid and endometrial biopsy, which showed some differences in the activity of many factors compared to the healthy control group [18].

Osteopontin

Osteopontin is a phosphorylated glycoprotein encoded by the SPP1 gene with a molecular weight ranging from 44 to 70 kDa, originally isolated from the bone matrix. In the course of further studies, the expression of osteopontin on cells such as NK cells, dendritic cells, macrophages, and bone matrix cells was discovered [19].

It consists of about 300 amino acids, has the ability to bind calcium, and also contains integrin-binding domains, which allows it to bind to many integrin receptors, and thus participate in numerous biological processes, such as adhesion, migration and cell activation.

Cellular secretion of osteopontin is believed to be modified by many different factors, such as vitamin D, interferon, and glucocorticoids. TNF-α and IL-1β affect the expression and transcription of the osteopontin gene, also taking part in its synthesis [20].

Due to its biological functions, osteopontin is involved in neoplastic processes, including those in the organs of the female reproductive system. It is believed to be a marker of ovarian epithelial carcinoma [21], endometrial carcinoma [22], and cervical squamous cell carcinoma [23].

It has been proven that this protein plays a role in the processes of angiogenesis [24], cell adhesion, apoptosis and in the development of the inflammatory process [25]. These processes are identical to the phenomena occurring during the development of endometriosis, hence the direction of research on the relationship between the development of endometriosis and the role of osteopontin seems to be interesting.

THE CURRENT STATE OF KNOWLEDGE

Due to the biological processes in which osteopontin is involved and their similarity to the processes involved in the pathogenesis of endometriosis, osteopontin is considered as a factor contributing to the development of the disease. There are also studies that say that osteopontin may be considered a marker of endometriosis.

Di Amico et al. [26] found an increased expression of the osteopontin gene in samples of endometriosis lesions from women suffering from it.

It has also been shown that osteopontin regulates the migration of stromal cells in the event of the development of endometriosis [27], and its serum levels are elevated in patients with this disease [28].

Osteopontin has been shown to be involved in cell adhesion and migration. It induces the invasion of endometrial cells into the stroma, thus promoting the formation of endometriotic implants. These phenomena are counted into the mechanisms taking part in promotion of the survival of endometriotic implants in the peritoneal environment outside the uterine cavity [29].

There are scientific studies that have shown an increased expression of osteopontin on the eutopic endometrium in women with this disease [30]. This observation seems to be a link between the theory of retrograde menstruation and the phenomenon of cell adhesion and could explain the situation of endometriosis only in some women in a situation where retrograde blood flow to the peritoneal cavity during menstruation takes place in about 90% of women.

Scientific research has shown that angiogenesis may play an important role in the pathogenesis of endometriosis. In endometriotic implants neovascularization occurs, which allows them to survive outside the uterine cavity. Vascular endothelial growth factor (VEGF) is considered to be the most potent factor involved in this process [31].

Importantly, there are reports that osteopontin can induce VEGF synthesis, thus increasing angiogenesis [32].

The study by SiHyun et al. [33] showed that the mRNA expression of the osteopontin gene in the eutopic endometrium and the level of osteopontin in the blood serum of patients are significantly higher in women suffering from endometriosis, which, according to the authors, may justify the use of osteopontin as a non-invasive disease marker. The same conclusions were drawn in the work of Yang et al. [34] also in this study, osteopontin is presented as a promising disease marker, and the authors confirmed their theses both in an animal model and in a group of patients with endometriosis.

The influence of the expression of the osteopontin gene on the functioning of various genetic signal pathways in which this protein is involved also seems interesting.

The analysis of microarrays in several studies showed an increased expression of the osteopontin gene both in endometrial tissues [35] and in the eutopic endometrium of women with endometriosis [34].

The altered expression of the OPN gene changes the activity of various signaling pathways involved in cellular processes. For example, activation of the PI3K/AKT pathway (phosphatidylinositol 3 kinase) and the secondary upregulation of uPA (urokinase plasminogen activator) may promote endometrial cell migration in patients with endometriosis, similarly to ovarian and lung cancers or head and neck cancers [35]. In addition, other authors have shown that increased expression of the osteopontin gene by affecting the expression of matrix metalloproteinase 9 (MMP 9) promotes the adhesion of endometrial cells to the stroma, and this phenomenon is additionally influenced by female sex hormones estrogens [34].

CONCLUSIONS

Endometriosis is a disease of unknown and complicated etiopathogenesis. Therefore, we are not able to cure the source of the disease, and the available therapeutic methods focus mainly on controlling its symptoms. At the present moment, there are also no specific markers of the disease, and is still the gold standard laparoscopy, which is an invasive procedure.

An obstacle to the use of osteopontin as a marker of endometriosis is its association with numerous disease processes that may coexist with endometriosis and thus lead to false-positive results.

Hence, research on osteopontin, which is involved in biological processes that may affect the development of endometriosis, seems to be promising when it comes to unraveling the mystery of the mechanisms of origin and treatment of this difficult disease entity.

Article information and declarations
Conflict of interest

The study received no financial support. The authors have nothing to disclose.

REFERENCES

  1. Appleyard TL, Mann CH, Khan KS. Guidelines for the management of pelvic pain associated with endometriosis: a systematic appraisal of their quality. BJOG. 2006; 113(7): 749757, doi: 10.1111/j.1471-0528.2006.00937.x, indexed in Pubmed: 16827756.
  2. Kennedy S, Bergqvist A, Chapron C, et al. ESHRE Special Interest Group for Endometriosis and Endometrium Guideline Development Group. ESHRE guideline for the diagnosis and treatment of endometriosis. Hum Reprod. 2005; 20(10): 26982704, doi: 10.1093/humrep/dei135, indexed in Pubmed: 15980014.
  3. Gao X, Outley J, Botteman M, et al. Economic burden of endometriosis. Fertil Steril. 2006; 86(6): 15611572, doi: 10.1016/j.fertnstert.2006.06.015, indexed in Pubmed: 17056043.
  4. Fernandez I, Reid C, Dziurawiec S. Living with endometriosis: the perspective of male partners. J Psychosom Res. 2006; 61(4): 433438, doi: 10.1016/j.jpsychores.2006.06.003, indexed in Pubmed: 17011349.
  5. Jones GL, Kennedy SH, Jenkinson C. Health-related quality of life measurement in women with common benign gynecologic conditions: a systematic review. Am J Obstet Gynecol. 2002; 187(2): 501511, doi: 10.1067/mob.2002.124940, indexed in Pubmed: 12193950.
  6. Meuleman C, Vandenabeele B, Fieuws S, et al. High prevalence of endometriosis in infertile women with normal ovulation and normospermic partners. Fertil Steril. 2009; 92(1): 6874, doi: 10.1016/j.fertnstert.2008.04.056, indexed in Pubmed: 18684448.
  7. Khawaja UB, Khawaja AA, Gowani SA, et al. Frequency of endometriosis among infertile women and association of clinical signs and symptoms with the laparoscopic staging of endometriosis. J Pak Med Assoc. 2009; 59(1): 3034, indexed in Pubmed: 19213374.
  8. Endometriosis and infertility. Fertility and Sterility. 2006; 86(5): S156S160, doi: 10.1016/j.fertnstert.2006.08.014.
  9. Revised American Fertility Society classification of endometriosis: 1985. Fertil Steril. 1985; 43(3): 351352, doi: 10.1016/s0015-0282(16)48430-x, indexed in Pubmed: 3979573.
  10. Yeung P. The laparoscopic management of endometriosis in patients with pelvic pain. Obstet Gynecol Clin North Am. 2014; 41(3): 371383, doi: 10.1016/j.ogc.2014.05.002, indexed in Pubmed: 25155119.
  11. Yeung P. The laparoscopic management of endometriosis in patients with pelvic pain. Obstet Gynecol Clin North Am. 2014; 41(3): 371383, doi: 10.1016/j.ogc.2014.05.002, indexed in Pubmed: 25155119.
  12. Seracchioli R, Mabrouk M, Guerrini M, et al. Dyschezia and posterior deep infiltrating endometriosis: analysis of 360 cases. J Minim Invasive Gynecol. 2008; 15(6): 695699, doi: 10.1016/j.jmig.2008.07.005, indexed in Pubmed: 18971131.
  13. Sampson J. Peritoneal endometriosis due to the menstrual dissemination of endometrial tissue into the peritoneal cavity. American Journal of Obstetrics and Gynecology. 1927; 14(4): 422469, doi: 10.1016/s0002-9378(15)30003-x.
  14. Jerman LF, Hey-Cunningham AJ. The role of the lymphatic system in endometriosis: a comprehensive review of the literature. Biol Reprod. 2015; 92(3): 64, doi: 10.1095/biolreprod.114.124313, indexed in Pubmed: 25588508.
  15. Matsuura K, Ohtake H, Katabuchi H, et al. Coelomic metaplasia theory of endometriosis: evidence from in vivo studies and an in vitro experimental model. Gynecol Obstet Invest. 1999; 47 Suppl 1: 1820; discussion 20, doi: 10.1159/000052855, indexed in Pubmed: 10087424.
  16. Diao R, Wei W, Zhao J, et al. CCL19/CCR7 contributes to the pathogenesis of endometriosis via PI3K/Akt pathway by regulating the proliferation and invasion of ESCs. Am J Reprod Immunol. 2017; 78(5), doi: 10.1111/aji.12744, indexed in Pubmed: 28856757.
  17. Ahn SH, Singh V, Tayade C. Biomarkers in endometriosis: challenges and opportunities. Fertil Steril. 2017; 107(3): 523532, doi: 10.1016/j.fertnstert.2017.01.009, indexed in Pubmed: 28189296.
  18. Fassbender A, O D, Moor BDe, et al. Biomarkers of Endometriosis. Endometriosis. 2014: 321339, doi: 10.1007/978-4-431-54421-0_20.
  19. Czemerska M, Robak T. Osteopontin regulator of angiogenesis and tumorigenicity. Acta Haematologica Polonica. 2010; 41(4): 453462.
  20. Icer MA, Gezmen-Karadag M. The multiple functions and mechanisms of osteopontin. Clin Biochem. 2018; 59: 1724, doi: 10.1016/j.clinbiochem.2018.07.003, indexed in Pubmed: 30003880.
  21. Cerne K, Hadzialjevic B, Skof E, et al. Potential of osteopontin in the management of epithelial ovarian cancer. Radiol Oncol. 2019; 53(1): 105115, doi: 10.2478/raon-2019-0003, indexed in Pubmed: 30712025.
  22. Al Maghrabi H, Gomaa W, Al-Maghrabi J. Increased osteopontin expression in endometrial carcinoma is associated with better survival outcome. Ginekol Pol. 2020; 91(2): 7378, doi: 10.5603/GP.2020.0020, indexed in Pubmed: 32141052.
  23. Cho H, Hong SW, Oh YJ, et al. Clinical significance of osteopontin expression in cervical cancer. J Cancer Res Clin Oncol. 2008; 134(8): 909917, doi: 10.1007/s00432-007-0351-5, indexed in Pubmed: 18210151.
  24. Asou Y, Rittling SR, Yoshitake H, et al. Osteopontin facilitates angiogenesis, accumulation of osteoclasts, and resorption in ectopic bone. Endocrinology. 2001; 142(3): 13251332, doi: 10.1210/endo.142.3.8006, indexed in Pubmed: 11181551.
  25. Denhardt DT, Noda M, O’Regan AW, et al. Osteopontin as a means to cope with environmental insults: regulation of inflammation, tissue remodeling, and cell survival. J Clin Invest. 2001; 107(9): 10551061, doi: 10.1172/JCI12980, indexed in Pubmed: 11342566.
  26. D’Amico F, Skarmoutsou E, Quaderno G, et al. Expression and localisation of osteopontin and prominin-1 (CD133) in patients with endometriosis. Int J Mol Med. 2013; 31(5): 10111016, doi: 10.3892/ijmm.2013.1325, indexed in Pubmed: 23545719.
  27. Fu X, Yao M, Ye C, et al. Osteopontin Regulates Endometrial Stromal Cell Migration in Endometriosis through the PI3K Pathway : Osteopontin Regulates Endometrial Cell Migration in Endometriosis. Reprod Sci. 2021; 28(2): 435446, doi: 10.1007/s43032-020-00301-8, indexed in Pubmed: 32909189.
  28. Cao Y, Liu X, Guo SW. Plasma High Mobility Group Box 1 (HMGB1), Osteopontin (OPN), and Hyaluronic Acid (HA) as Admissible Biomarkers for Endometriosis. Sci Rep. 2019; 9(1): 9272, doi: 10.1038/s41598-019-45785-w, indexed in Pubmed: 31239500.
  29. Vercellini P, Viganò P, Somigliana E, et al. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol. 2014; 10(5): 261275, doi: 10.1038/nrendo.2013.255, indexed in Pubmed: 24366116.
  30. Hapangama DK, Raju RS, Valentijn AJ, et al. Aberrant expression of metastasis-inducing proteins in ectopic and matched eutopic endometrium of women with endometriosis: implications for the pathogenesis of endometriosis. Hum Reprod. 2012; 27(2): 394407, doi: 10.1093/humrep/der412, indexed in Pubmed: 22147918.
  31. Marí-Alexandre J, García-Oms J, Barceló-Molina M, et al. MicroRNAs and angiogenesis in endometriosis. Thromb Res. 2015; 135 Suppl 1: S38S40, doi: 10.1016/S0049-3848(15)50439-8, indexed in Pubmed: 25903532.
  32. Du J, Mao H, Ouyang H, et al. Osteopontin induced vascular endothelial growth factor production in dispersed nasal polyp cells through the phosphatidylinositol 3-kinase-protein kinase B and the extracellular signal-regulated kinase 1/2 pathways. Am J Rhinol Allergy. 2017; 31(4): 3541, doi: 10.2500/ajra.2017.31.4449, indexed in Pubmed: 28716167.
  33. Cho S, Ahn YS, Choi YS, et al. Endometrial osteopontin mRNA expression and plasma osteopontin levels are increased in patients with endometriosis. Am J Reprod Immunol. 2009; 61(4): 286293, doi: 10.1111/j.1600-0897.2009.00692.x, indexed in Pubmed: 19260859.
  34. Yang M, Jiang C, Chen H, et al. The involvement of osteopontin and matrix metalloproteinase- 9 in the migration of endometrial epithelial cells in patients with endometriosis. Reprod Biol Endocrinol. 2015; 13: 95, doi: 10.1186/s12958-015-0090-4, indexed in Pubmed: 26289107.
  35. Fu X, Yao M, Ye C, et al. Osteopontin Regulates Endometrial Stromal Cell Migration in Endometriosis through the PI3K Pathway : Osteopontin Regulates Endometrial Cell Migration in Endometriosis. Reprod Sci. 2021; 28(2): 435446, doi: 10.1007/s43032-020-00301-8, indexed in Pubmed: 32909189.