What are Biomarkers?

Biomarkers are a class of markers related to cell growth and proliferation that have been proposed with the development of immunology and molecular biology technology in recent years.

Chinese name: Biomarker
Foreign name: Biological markers

Function: Markers related to cell growth and proliferation
Application: Clinical application

Basic introduction of biomarkers

Biomarker ^[1] not only can explore the pathogenesis at the molecular level, but also has a unique advantage in accurately and sensitively assessing early and low levels of damage. It can provide early warning and largely provide clinicians with The basis of auxiliary diagnosis.

Biomarker metabolic marker

Biomarker bone metabolism marker

By measuring the levels of pyridinoline (PYD) and type I collagen N-terminal cross-linked peptide (NTX-I) and C-terminal cross-linked peptide (CTX-I) in urine, the metabolism of bone type I collagen can be reflected. The study found that PYD levels were significantly increased in patients with OA, and the levels of CTX-I in urine of patients with advanced OA were significantly higher than those in the control group. Serum calcitonin as a marker reflecting bone synthesis has shown inconsistent results in studies of OA patients.

Utilizing existing bone metabolism markers to reflect the unsatisfactory condition of OA. More scholars are working to find more specific and sensitive markers that reflect cartilage and synovial metabolism.

Cartilage metabolism markers

The anabolic metabolism of cartilage type II collagen can be reflected by the detection of several markers. Among them, the type II collagen carboxypeptidone (CTX-) is the most important. Multiple studies have confirmed that urine CTX- levels are significantly elevated in patients with 0A and RA. By measuring serum PIICP (procollagen type C-terminal propeptide), it was found that type collagen synthesis increased in the early stages of OA. Rousseau [2] used ELISA to measure PIIANP and found that its level was reduced in OA patients. Deberg [3] found that two degradation products of cartilage type II collagen peptides: Coll2-1 and Coll 2-1 NO2 levels were elevated in OA patients. Charni [4] found that urine HELIX- levels were significantly higher in patients with knee OA than in healthy controls. Table 1 BIPED classification of bone, cartilage, and synovial metabolic markers Tissue molecular synthesis markers Degradation markers BIPED classification methods Bone type collagen

Clinical application of biomarkers

Biomarker diagnostic marker

Although the levels of most markers (CTX-, COMP, PYD, etc.) in the current study were significantly increased in most OA individuals, they showed normal levels in a certain proportion of patients. This suggests that these markers alone are not sufficiently sensitive as a diagnostic tool for OA. Elevated blood COMP has been observed to be associated with hip-related symptoms (pain, stiffness) in patients without characteristic features of hip OA imaging, but not found in patients with knee OA. COMP and NTX-I were found to be related to the imaging progress of elderly women with OA. In women with postmenopausal knee OA who had imaging findings for more than 4 years, COMP and NTX-I levels increased. The study found that in patients with knee trauma, PIICP levels in synovial fluid increased in the early stages of cartilage degradation that was not manifested on X-ray but had been found under arthroscopy. Chevalier found CTX- in synovial fluid. Levels increased in the early stages of OA with no imaging findings, and their levels rose as much as three times compared to the control group.

In conclusion, although some markers may be significantly elevated in the early stages of OA, these markers lack specificity and cannot be used for the diagnosis of individual OA patients alone due to their lack of sufficient sensitivity.

Biomarker disease severity marker

The disease of disease markers (burden of diseasemarkers) mainly assess the severity or extent of OA, especially the disease at a certain point in time. In a study of 71 female OA patients, CRP, PYD, YKL-40, MMP-3, and nMP-1 levels were significantly higher in patients with systemic multiple OA than in patients with knee OA alone. Elliott found in a large study of multi-ethnic sample cases that HA levels in white races were significantly higher than in black races, with men higher than women. Another study of 291 white knee OA patients found that blood COMP levels increased significantly with increasing KL (Kellgren-Lawrence grades) scores. In a study of 324 postmenopausal women, Garnero found that the levels of CTX- in urine of patients with OA in different parts were also different, suggesting that this could identify OA in different parts.

The markers used to assess the severity of the disease are similar to those used for diagnosis, so most of them belong to both types of markers. Because OA is often present in more than one site and is often accompanied by different degrees of superimposition of the symptoms of various sites, disease severity markers are currently only used in clinical research and cannot be accurately reflected by individual markers in individual patients. Severity of the disease.

Biomarker disease prognosis marker

Studies have found that CTX-I and serum calcitonin levels are higher in patients with advanced OA than in patients with non-progressive or control phase, but other studies have yielded opposite results. This may be because the bone metabolism markers not only reflect the subchondral bone abnormalities caused by OA, but also reflect the bone metabolism of the whole body, so they are susceptible to age, menopause, osteoporosis and other skeletal system diseases.

In a study of 172 patients with primary knee OA with a course of more than 4 years, PIICP levels of type II collagen metabolites in the synovial fluid of patients with advanced stages were significantly higher than those of patients with non-progressive stages. The Rotterdam Research Center followed up 1,235 patients with knee and / or hip OA for 6.6 years and found that elevated levels of CTX- and HELlX- were closely related to the prevalence and disease progression of knee and hip OA. In another study of 333 patients with hip OA, patients with high levels of CTX-II and HA were associated with rapid progression of imaging disease. Deberg [9] found that high levels of Coll2-l and Coll2-l NO2 in urine of patients with knee OA for more than 1 year can predict the changes of joint space stenosis in the next 3 years. Pavelka followed up 89 patients with knee OA for 2 years and found that the high basal state of HA was related to the rapid progression of OA imaging. Sharif's follow-up of 115 patients with knee OA found that the basic level of COMP in advanced patients was significantly higher than that in non-progressive patients. Garnero followed up 75 patients with knee OA for one year and found that patients with low PIIANP levels and high CTX- levels had 8 times faster knee damage than the control group. In a study of 230 patients with knee OA, it was found that the measurement of basal levels of type II collagen metabolites (C2C, PIICP, C1, 2C, PIICP) can predict OA imaging progression over 18 months.

Because in OA patients, joint injuries include bone, cartilage, and synovium, it is necessary to use a combination of several markers to predict the prognosis of the disease.

Biomarker efficacy marker

The BRISK Research Center found in a 1-year prospective study of 186 patients with mild to moderate OA that urinary CTX- levels were significantly reduced after treatment with diphosphates. In a study of 20l patients with knee OA, urine CTX-II levels decreased after treatment with nonsteroidal anti-inflammatory drugs. Garnero achieved similar results in another group of knee OA patients treated with COX-2 inhibitors.

In a study of 212 patients with knee OA, Christgau found that patients with high CTX-II basal levels had a significant decrease in CTX- levels after more than 3 years of treatment with glucosamine sulfate. In a study of 301 postmenopausal women with OA, selective estrogen receptor modulators significantly reduced urinary CTX-II levels. Manicourt found that in patients with knee OA, urine CTX-, C2C, and MMP-1,3 levels decreased significantly after salmon calcitonin treatment.

Once the evaluation of OA patients' response markers to chondroitin active drug therapy is improved, biomarkers may provide more information about the effect of treatment on cartilage circulation, which will greatly complement and improve the information provided by clinical and imaging studies. .

Biomarker research marker

Investigative markers are a class of markers that are not included in other classifications with sufficient basis. Markers obtained by new research methods can fall into this category. For example, studies have found that a novel marker in urine that is closely related to knee and hip OA can be attributed to this category. However, several studies on genes encoding articular cartilage and extracellular matrix proteins have not yet provided sufficient evidence to confirm that nonsynonymous mutations in these genes are risk factors for primary OA. The clinical application of research markers is yet to be seen, but they provide new information on the pathogenesis of OA and have potential clinical applications.

Biomarker research conclusions

In previous studies on OA markers, the type II collagen degradation product CTX-II seems to be one of the most promising markers to date [6-8, 12-16]. Due to the large number of polymerizable proteoglycans in cartilage and their important role, the combined measurement of type II collagen and cartilage polymerizable proteoglycan synthesis and metabolites may provide more effective information than a single measurement of a single marker, and found that a series of high sensitivity, The combination of specific biomarkers and simple and effective detection methods for early diagnosis of OA, monitoring disease progression, and assessing prognosis will be future research directions.