Osteoprotegerin(OPG) also known as TNFRSF11B is a member of the TNFR(tumor necrosis factor receptor) superfamily proteins. It is an important factor in many biological processes. Its role appeared to be of particular importance in bone turn-over metabolism, inflammation, tumorgenesis and other processes where cell differentiation, survival and death are controlled[1-3].
OPG was discovered as a protein that fulfils a major role in bone metabolism[4,5]. Additionally, several authors found OPG to play a role in gastrointestinal inflammation[11-15]. Especially in Crohn’s disease(CD)[12-14] and ulcerative colitis(UC), both inflammatory bowel diseases(IBD). Moreover, OPG also has a certain role, however less investigated than in IBD, in gastrointestinal types of cancer[1,3], like colon carcinoma[16-18] and gastric carcinoma. In this review we describe the functional role of OPG related to IBD and gastrointestinal forms of cancer.
OPG was separately identified by two groups in 1997[4-5]. Both authors[4-5] found that OPG has a major role in bone metabolism by inhibiting osteoclastogenesis. Initially, they were identified as OCIF(osteoclastogenesis inhibitory factor) and OPG. However, in 1998 they were found to be the same. Due to its dominant role by inhibiting osteoclastogenesis the ASBMR(American Society for Bone and Mineral Research) decided in 2000 to use osteoprotegerin(OPG) as the official name.
OPG its mature structure contains of 380 amino acids located on chromosome 8q23-24. OPG its molecular structure has seven domains that can be specified[8,9]. The first four domains (D1-D4) contain cystin-rich structures at the N terminus. The fifth and the sixth domain (D5 and D6) are death-domains while the seventh domain is a C-terminus heparin-binding site. The cystin-rich domains are required to inhibit osteoclast differentiation. The death-domains their physiological function is still unclear however they proved to play a role in cytotoxic signals. The cys-400 located in domain seven is of importance in homodimerization and glycosaminoglycan linkage[8,9]. The homodimeric form of OPG has been found to be most active.
OPG in RANKL/RANK linkage
As a member of the TNFR superfamily proteins OPG has an important role in several pathways where NF-??B is involved. Receptor activator of nuclear factor (NF)-??B ligand (RANKL) and receptor activator of nuclear factor (NF)-??B (RANK) form a complex that induces osteoclastogeneis in bone. RANKL is expressed on the surface of osteoblasts where it binds to RANK that is expressed on the surface of osteoclast progenitor cells. The RANK-RANKL linkage is responsible for osteoclast development and increases osteoclast activity and therefore stimulating bone breakdown[20,21].
Also, RANKL is one of the ligands OPG can bind to[22,23]. OPG is secreted by osteoblasts and acts as a decoy receptor, in its highly active homodimeric form, by binding to RANKL[4,5]. In this way OPG prevents RANKL from binding to RANK. It was therefore found that OPG, by binding to RANKL, inhibits osteoclastogenesis and decreases osteoclast activity[4,5].
Studies with knock-out mice confirm the role of OPG in bone homeostasis. Osteopetrosis was developed in RANKL-/- knock-out mice, where osteoporosis was developed in OPG-/- knock-out mice. Thus, the OPG/RANKL/RANK pathway plays a major role in bone metabolism.
As OPG prevents RANKL from binding to RANK it was suggested that OPG could play a role in other tissues other than bone tissue. In addition, OPG is synthesised in dendritic cells(DC) and B-lymphocytes where RANKL mainly is produced in T-lymphocytes[25-28]. Moreover, cytokines, CD40-CD40L and RANKL induce the synthesis of OPG in immune cells[27,29].
RANKL-RANK linkage activates several pathways that contribute to the survival of T-lymphocytes and dendritic cells. OPG, as in bone tissue, prevents RANKL-RANK interactions and has a role in the immune system similar to its role in bone tissue. OPG-RANKL linkage down regulates T-lymphocytes and DC activity and decreases therefore inflammation. In their turn, cytokines, TNF-?? and INF-??, enhance OPG synthesis in osteoblasts and inhibit function of both osteoblasts and osteoclasts respectively[29,30].
OPG and TRAIL
OPG its role appears to be important in overall cell survival. In addition, OPG has a role in the TNF-related apoptosis inducing ligand (TRAIL) pathway. TRAIL is a ligand that induces apoptosis. OPG has the ability to bind to TNF-related apoptosis inducing ligand (TRAIL) and inhibits its activity. However, TRAIL its cytotoxicity does not influence healthy cells. Therefore it is suggested that OPG can extend cell survival, particularly in tumour cells in different types of cancer[33,34] including gastric and colon carcinoma.
The TRAIL induced apoptosis pathway has been described by several authors[63-65]. TRAIL has the ability to bind certain death receptors(DR4 and DR5) located on cell surface walls[63-65]. After TRAIL has bound to these death receptors an apoptosis pathway will be initiated. With main roles for caspases, Bcl-2 and the p53-gene cell death will occur[66,67]. Next to DR4 and DR5 there are three decoy receptors(DcR1, DcR2 and OPG) found to inhibit binding TRAIL to either DR4 or DR5[66-67]. DcR1 and DcR2 are also expressed at the cell surface where OPG is expressed in a soluble form. When TRAIL is bound to one of the three decoy receptors cells can escape cell death. Thus, OPG can act as a protector of apoptosis and extends tumour cell life[16,19,33,34] .
TRAIL is produced by several immune cells[68,69]. Therefore the role of TRAIL is not only considered to be involved in inducing apoptosis pathways in tumour cells but TRAIL is also involved in immune surveillance. In addition, important regulators of TRAIL are interferons(IFN)(e.g. IFN-??, ??, ??)[70,75]. TRAIL was also found in patients suffering IBD. TRAIL was suggested to be responsible for disruption of intestinal epithelium by apoptosis of enterocytes.
TRAIL not only participates in tumour cells and inflamed cells but also has a role in bone turn-over homeostasis. TRAIL inhibits osteoclast differentiation and induces apoptosis in osteoclasts[72,73]. Paradoxically, OPG protects osteoclasts from apoptosis whilst it, as aforementioned, decreases osteoclastogenesis by binding to RANKL. OPG, TRAIL and RANKL are therefore key regulators in processes that contain disease state, success of treatment and cell survival.
OPG and RANKL levels in IBD
IBD, describing CD and UC, is best hypothesised as an inflammation of the intestinal mucosal induced by activation of either innate and/or adaptive immune systems. Immune cells, like T-cells and macrophages, produce pro-inflammatory cytokines including TNF-??, interleukines(IL-1, IL-2, IL-6 and IL-8) and other chemokines. These proteins are all centrally regulated by the NF-??B pathway and activate or perpetuate inflammation[48-50].
Franchimont et al. found that OPG and sRANKL(RANKL its soluble form) were significantly higher in the serum of CD patients. OPG (23,7 pg/mg mL) and RANKL(1,03 pg/mg mL) levels were also significantly higher in colonic supernatant biopsies in comparison to controls(6,6 pg/mg mL; P=0,0016 and 0,46 pg/mg mL;P=0,0066 respectively). In addition, N. Franchimont et al. found that OPG levels significantly correlate with pro- and anti-inflammatory cytokines(TNF-??, IL-1??,6,10) and therefore suggest that OPG is enhanced by cytokines as a result of chronic inflammation. sRANKL did not correlate with any cytokine. The up-regulated sRANKL that was both found in serum as in colonic mucosa may contribute to an increased amount of activated T-lymphocytes.
Moschen et al. did a similar research as Franchimont et al did. They compared 112 IBD patients to 45 controls. They found significantly up-regulated levels for OPG but not for sRANKL in serum. In inflamed colonic mucosa Moschen et al found significant higher levels of OPG in both CD and UC patients. sRANKL levels were not enhanced in neither CD nor UC inflamed colonic mucosa in comparison to control colonic mucosa. Moschen et al also found significant positive correlations between OPG and leucocytes and platelets. OPG was negatively, though significant, correlated with erythrocytes and haemoglobin.
OPG+-cells were found in CD and UC samples by immunohistochemical localisation, specifically in epithelial cells and the lamina muscularis. A few OPG+-cells were found in controls, however significantly lower than in inflamed colonic mucosa. RANKL+-cells were both found in control subjects as in CD and UC subjects and there was no significant difference. As RANKL levels are only enhanced in early colitis and OPG levels start to increase later on in colitis this may explain the not significantly raised sRANKL levels. Another explanation could be that only free RANKL(sRANKL) can be measured. RANKL that is bound to either OPG or RANK is not measurable meaning that the total proportion RANKL may be underestimated by measuring sRANKL only.
As the increased amount of immune cells and cytokines in IBD correlate with increased levels of RANKL, many authors suggest that IBD correlates with osteopenia and osteoporosis[14,37,38]. Therefore OPG may function as a counter mechanism to protect bone loss and decrease inflammation[15,38] as OPG decreases osteoclast activity as well as DC activity[15,38].
In a recent study L. Nahidi found TNF-?? to increase OPG levels in two colonic epithelial cell lines(HT-29 and Caco-2). In this in vitro study they compared untreated epithelial cell lines its OPG levels(HT-29: 400 ??25 pg/mL; Caco-2: 368 ??44 pg/mL) with OPG levels in TNF-??(100 ng/mL) treated epithelial cell lines (HT-29: 3,596 ??294 pg/mL; Caco-2: 3,609 ??210 pg/mL)(P<0,01). TNF-?? significantly increased OPG levels in both cell lines. They also found IL-8 levels to increase in both cell lines after stimulated with OPG levels as were measured in CD patients (1000 pg/mL' OPG level ' 10,000 pg/mL)(P<0,01). The activation of the NF-??B pathway by OPG and TNF-?? was also studied by L. Nahidi et al.. NF-??B is usually inhibited by I??B. NF-??B is activated by inhibiting I??B by a I??B-kinase, I'?-??[48-50]. In both cell lines treated with OPG(10,000 pg/mL) and TNF-??(100 ng/mL) they found NF-??B its activator I'?-?? to have been increased. By measuring tight junction proteins occludin, claudin-1 and zona occludens-1(ZO-1) L. Nahidi et al also found all three proteins levels to have been decreased after stimulating both cell lines with similar levels of OPG and TNF-??. When compared to untreated cell lines the decrease of all three proteins was found to be significant(P<0,01). This decrease is related to loss of gut function. Earlier studies found that loss of gut function is related to pro-inflammatory cytokines in IBD[48,53]. All studies described that OPG has a major role in inflammation pathways, mucosa integrity and tight junction function in IBD. It either activate or/and perpetuate inflammation in the gut by stimulating immune cells, cytokines and the NF-??B pathway. OPG as novel biological marker in IBD treatment Several authors studied OPG as a novel biological marker in IBD treatment[35,39,40]. Miheller et al studied OPG, RANKL and bone marker levels in CD patients while patients were following an infliximab treatment. They included 29 CD patients. 65,51% reacted on infliximab. This was measured by the CD activity index(CDAI) and number of fistulas. Both CDAI and fistulas showed a decrease in score and amount, respectively, after 42 days of infliximab treatment. In responders, OPG levels decreased(P<0,05) and osteocalcin levels, a bone synthesis marker, increased(P<0,05) after 42 days. It was suggested that infliximab has an indirect effect on OPG, operating via decreasing TNF-?? and therefore decreasing OPG synthesis in osteoblasts[29,39] Sylvester et al studied the role of faecal OPG in paediatric UC patients while treated with corticosteroids. They enrolled 83 children in the study. 61 patients responded to corticosteroids treatment measured by criteria of individual clinicians and measured by disease activity according to the Paediatric Ulcerative Colitis Activity Index(PUCAI). Faecal OPG was compared with PUCAI, C-reactive protein(CRP), albumin and stool frequency. At day 3 of the treatment faecal OPG levels of non-responders were significantly higher than levels in responders(77 pmol/L versus 13 pmol;P=0,007). At day 3, the correlation between OPG and serum albumin(P=0,014), CRP(P=0,04) and PUCAI(P=0,001) was also significant(P=0,001.These outcomes suggest that faecal OPG is a predictor of ulcerative colitis activity. OPG is not only a predictor of ulcerative colitis activity, but it is also a better predictor than other faecal biological markers as S100A12, Calprotectin and Lactoferrin. In addition, OPG indicates another inflammation pathway than other faecal markers do. Where S100A12, lactoferrin, calprotectin are secreted by neutrophils[42-45], OPG is produced by intestinal epithelial cells and dendritic cells[12,46]. In comparison with other studies[42-45], Sylvester et al found OPG to be a better indicator of success of treatment. OPG, as predictor of UC activity, was comparable to M2-pyruvate kinase(M2-PK). OPG might be useful as a biological marker as it distinguishes among several inflammation pathways in IBD. As OPG is significantly increased in UC paediatric patients but not in CD paediatric patients it was suggested that OPG can fulfil a role, as a marker, in distinguishing UC from CD in paediatric patients . Skinner et al included 22 paediatric patients (UC=7, CD=5, Control=10). They found that OPG levels in stool were significantly higher in UC patients than in CD or controls (UC: mean: 114 pmol/L ?? SD:226 [median: 31]; CD: mean: 0.6 pmol/L ?? SD: 0.8 [median:0.2]; Control: mean: 1.7 pmol/L ?? SD: 2.8 [median: 0.6]). Serum OPG did not correlate with both UC and CD. However, limitation of this study is the low number of patients included (UC=7, CD=5, Control=10). L.Nahidi et al studied OPG levels of serum, mucosal biopsies and faeces in newly diagnosed paediatric CD patients. They found that serum OPG levels do not correlate with CD(P>0,05). However, when stratified in a mild CD group and a moderate/severe CD group, serum OPG levels were significantly elevated for the moderate/severe group(1246 pg/mL ??586;n=16) compared to controls(879 pg/mL ?? 232;n=28)(P=0,005). OPG levels were significantly elevated in mucosal biopsies in CD patients(14,317 pg/mL ??15,095; n=11) compared to controls(677 pg/mL ??676 pg/mL; n=9)(P=0,018). Faecal OPG levels were significantly elevated in both moderate/severe CD patients(6464 pg/mL ??869;n=17) and mild CD patients(477 pg/mL ??848;n=22) compared to controls(63 pg/g ?? 0,001;n=8)(P<0,0001). Furthermore, faecal levels of OPG correlated with disease location. Patients with colonal inflammations showed higher OPG levels(4232 pg/mL ??8037) than patients with ileocolonal inflammations(98 pg/mL ??280)(P=0,022). L. Nahidi et al also studied the effect of exclusive enteral nutrition(EEN) treatment on OPG levels in newly diagnosed paediatric CD patients. EEN treatment proved its beneficial effect on paediatric CD patients[54,55]. Faecal OPG levels dropped significantly after 6-8 weeks EEN-therapy(1994 pg/mL ?? 2289 to 406 pg/mL ??551;P=0,002) but where still significantly elevated in comparison to controls(P=0,005) Serum OPG levels significantly dropped as well(1683 pg/mL ??932 to 1099 pg/mL ??883,6)(P=0,0001). Interestingly, S100A12 and CRP, both functioning as markers in disease activity in IBD, correlated with OPG before treatment(P=0,002 and P=0,038 respectively) but after treatment correlation was not significant anymore(P=0,29 and P=0,72 respectively). The success of EEN-treatment can be found in inducing mucosal pro-inflammatory mediators, up-regulating anti-inflammatory cytokines in the mucosa, supressing the NF-??B pathway and thereby inducing mucosal healing[54,55,57]. These mechanisms could explain the drop-down of OPG levels after EEN-treatment. Thus, OPG levels in serum, mucosa and faeces correlate with both CD and UC[12,35,39-41,52,58]. IBD its severity and disease location also correlate with elevated OPG levels[40,58]. Studies to OPG levels in IBD treatment, respectively infliximab, corticosteroids and exclusive enteral nutritional treatment, all showed a significant drop in OPG levels[39,40,58]. Therefore OPG can possibly be used as a novel biological biomarker in IBD. Not only the onset and diagnosis of IBD can be determined, also IBD could be managed during treatment by measuring OPG. Furthermore, one study showed a difference in OPG levels between CD and UC in children. Therefore it might be possible to diagnose either CD or UC by measuring OPG and point out the pathological difference between both diseases. Another difference was also found between OPG levels and other biological markers while suffering IBD[40.58]. This could mean that OPG has a different role in inflammation pathways than other biological markers have. This difference might be useful in distinguishing inflammation pathways and select an appropriate treatment. However, it is still unclear what OPG exactly predicts. Whether it only predicts IBD onset, its severity, its location, success of treatment, a difference between CD and UC or all of that is still unclear. A second inexplicable difference in OPG levels is the difference between OPG levels in adults and children suffering IBD. Several studies found a clearer role, especially in the serum, for OPG in adults than in children as both sRANKL levels and OPG levels altered among studies conducted in children. An explanation for this difference could be the major role that OPG and RANKL play in bone metabolism. Bone tissue turn-over is rather more dynamic in children than in adults and therefore OPG and RANKL levels could differ more frequently than in adults. Therefore one can discuss the role of OPG in disease management in paediatric IBD. A third still unknown phenomenon is the correlation among several other biological markers used in IBD management. Several studies studied the correlation among S100A12, lactoferrin, calprotectin and M2-PK. OPG, unfortunately, was never included. As OPG was found to be of particular value in IBD management it is recommended to start studying the role of OPG in IBD and its management according to other biological markers. A fourth point of interest that has to be studied more is the best way of measuring OPG levels. It is not yet clear whether serum, mucosa or faeces show the best reflection of OPG in IBD. Further research should contain the mentioned impairments of OPG in IBD. Most interesting is that there is role for OPG in IBD. What that exact role is and how that can be used in IBD disease management needs further research. OPG and gastrointestinal cancer OPG has, next to the role it has in bone turn-over homeostasis and the immune system, also a role in cancer. It has been found that OPG has a role of particular interest in several cancers, like prostate cancer, breast cancer, colon cancer, multiple myeloma and other cancers[1,3,16,33,60]. OPG has a role in protecting tumour cells against apoptosis by TRAIL. OPG inhibits TRAIL from inducing apoptosis in tumour cells and is therefore a pro-tumour factor[16,33,60]. Paradoxically, OPG has also an anti-tumour effect on bone metastasis where it protects against osteolysis and bone tumour growth in bone[61,62]. As OPG fulfils several roles in carcinogenic pathways, OPG might play a role in pathological development of cancer. The role of OPG in gastrointestinal cancers like colon and gastric cancer has been investigated in some studies and will be highlighted in the next paragraphs. The role of OPG in gastrointestinal cancer TRAIL, which induces apoptosis, has been found in both gastric and colon carcinoma cells[74-77]. Normal colon tissue was found to be resistant to TRAIL and its apoptosis. A few authors studied the role of OPG in gastric and colon carcinoma cells after TRAIL was found to contribute to tumour cell survival[33,60-62]. Ito et al were the first that study the role of OPG in gastrointestinal cancers. They conducted a study to OPG in gastric carcinoma. They included 103 patients suffering gastric carcinoma and studied OPG expression in the obtained tumour tissues. They placed all tissues in three groups according to disease state. After that, they analysed all tissues by using immunohistochemistry to detect OPG and using reverse transcription polymerase chain reaction(RT-PCR) to detect OPG mRNA. Then, those findings were compared to disease state such as tumour invasion depth, state of tumour, lymph-node metastasis and prognosis. In all three gastric carcinoma tissues OPG was detected whilst it was not seen in non-neoplastic epithelial cells. Also, elevated OPG expression analysed by immunohistochemistry was correlated with deeper invasion of tumour cells(P<0,001), more nodal metastasis(P<0,001) and higher cancer stages(P=0,023).. In addition, patients expressing a higher OPG level were found to have a significant decline in survival rate after undergoing surgery(P=0,008). However, the strongest predictor of survival was not OPG but tumour stage. Therefore it is not sure of OPG directly correlates with disease state and prognosis but OPG may fulfil a role as a marker. A next study to gastrointestinal cancer was done by Pettersen et al. They studied OPG in colon carcinoma cells. They cultured human colon carcinoma cells(HT-29 and SW-480) and found in both cell lines expression of OPG mRNA and OPG measured by RT-PCR and ELISA respectively whereas no presence of OPG was found in controls. Pettersen et al also found that OPG was up-regulated in colon carcinoma cells after stimulated with inflammatory cytokines(TNF-?? and IL-1). Franchimont et al already found this up-regulation of OPG by inflammatory cytokines in IBD. Pettersen et al suggest that tumour stromal cells, like macrophages and fibroblasts, are responsible for secreting these cytokines. In this way colon carcinoma cells might protect themselves against apoptosis by secreting inflammatory cytokines. An opposite effect was found by Pettersen et al when treated colon carcinoma cell cultures with TRAIL in the presence of RANKL. The number of colon carcinoma cells decreased significantly(P=not known) in comparison to cultures without presence of RANKL. This suggests that RANKL might bind to OPG and inhibits OPG its role in inhibiting TRAIL-induced apoptosis. Another study was done by De Toni et al. They included 40 healthy controls and 127 patients suffering colorectal cancer(CRC). Those 127 patients were divided according to disease state indicated by the International Union Against Cancer(IUCC)(n=10 IUCC I, n=34 IUCC II, n=43 IUCC III, n=40 IUCC IV). OPG was again found to be elevated in CRC cells in comparison to healthy controls. They also found a significant higher serum level of OPG in patients with stages UICC III and IV in comparison to healthy controls(UICC III P=0,0359;UICC IV P<0,0001). When they compared serum levels of UICC III to UICC IV serum levels an even higher significance was found(P<0,00001). As the UICC IV-group contains metastatic CRC patients this might be related to bone metastases[61,62]. However, only one out of forty suffered bone metastasis where most suffered liver metastases. A role for bone metastasis in contributing to elevated OPG serum levels in CRC is therefore not plausible. De Toni et al also found that CRC cells are sensitive to adding either TRAIL or/and OPG. When added TRAIL more apoptosis was registered. When later on OPG was added next to the already added TRAIL less apoptosis was noticed. Moreover, both effects were dependent on either TRAIL or OPG concentration. Thus, OPG and TRAIL may fulfil a role as target in cancer treatment. De Toni et al also found ??-catenin, a protein associated with many diseases and cancer, fulfilling a role in regulating OPG and therefore inhibiting TRAIL-induced apoptosis as well. When ??-catenin was silenced, an increase of TRAIL-induced apoptosis was found. The most recent study to OPG in CRC has been carried out by Tsukamoto et al. They studied the clinical significance of OPG in CRC and included 274 patients suffering CRC. They found OPG mRNA to be more elevated in the metastatic group where OPG was less elevated in to the non-metastatic group(P=0,035). By immunohistochemistry they detected OPG in CRC epithelial cells. These results, as in OPG mRNA and immunohistochemical OPG, are congruent with the results of Ito et al in gastric carcinomas. Next, 274 patients were divided in two groups depending on OPG staining score(n=135 in low OPG expression group; n=139 in high OPG expression group). Significant correlations were found in the high-expression group for deeper tumours(P=0,002), lymphatic node invasion(P=0,026), lymphatic node and distant metastasis(P=0,001;P<0,001), higher carcinoembryonic antigen levels(CEA)(P<0,001), a lower overall survival rate(P<0,001) and a lower relapse-free survival rate(P=0,001) when compared to the low-expression group. These results suggest that OPG expression worsens tumour progression, metastasis and survival rates in CRC. All above studies found that a higher level of OPG in serum, colon carcinoma cells and gastric carcinoma cells correlate with a worse prognosis in both colon cancer and gastric cancer. Higher levels of OPG are related to deeper tumour invasion, metastasis and a lower survival rate. Especially, as shown by De Toni et al, a very significant difference is seen between metastatic CRC/UICC IV stage and lower stages. However it is still unclear if OPG affects gastrointestinal cancer directly as there are more factors influencing TRAIL. Again, as in IBD, inflammatory cytokines and the OPG/RANKL/RANK pathway have influence on the activity of OPG. All of these factors make the role of OPG, as a predictor of gastrointestinal cancer prognosis and treatment, undetermined. The last years several authors studied the role of TRAIL and OPG in cancer treatment. Results are promising and therefore OPG and TRAIL are not only important as a novel biological marker but both also may fulfil a role in cancer treatment[80,81]. When treating cancer it is of great importance to know what kind of treatment would benefit most. A lot of treatments benefit, like adjuvant chemotherapy, but also have a lot of toxic side effects. As OPG correlates with a lot of tumour characteristics, OPG, like in IBD, has the probability to function as a biological marker in gastrointestinal cancer and may predict the efficiency of gastrointestinal cancer treatments. Studies to other forms of cancer found OPG to be promising in its role of a biological marker and in that way predicting success of treatment[33,60,62,78,79]. However, OPG its role in gastrointestinal cancer has not been studied widely. It is therefore of particular importance commencing more studies to the role of OPG in gastrointestinal cancer. Conclusion OPG is a multifunctional factor in several pathways. OPG fulfils a role in bone turn-over metabolism, inflammation and cancer. All-encompassing OPG fulfils an important role in cell survival. It participates in TRAIL, RANK/RANKL, NF-??B-pathway and other pathways. As OPG influences more than one of these pathways at the same time inflammation, tumour activity and bone metabolism cannot be analysed separately. OPG is not only influencing mentioned pathways but is also influenced by many different pathways. Therefore, OPG is an interesting protein to research but also a difficult phenomenon. Evaluating the use of OPG as a novel biological marker was the main purpose of this review. It was found that OPG predicts, indicates and initiates many pathways and it is therefore difficult to use OPG as a direct reflection of disease management. However, OPG is a key factor in many processes and therefore promising to fulfil a role as a biological marker. In both IBD and gastrointestinal cancer OPG showed to indicate disease severity and success of different treatments. Measuring of OPG might be promising in choosing an appropriate treatment for both IBD and gastrointestinal cancer. OPG may be also of particular value in studying inflammation pathways in IBD and tumour cell survival pathways in gastrointestinal carcinoma. However, more research, especially to OPG its role as a biological marker in IBD and gastrointestinal carcinomas, needs to be done
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