CN111394448A - Application of Progranulin as biomarker in preparation of product for diagnosing postmenopausal osteoporosis - Google Patents

Application of Progranulin as biomarker in preparation of product for diagnosing postmenopausal osteoporosis Download PDF

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CN111394448A
CN111394448A CN202010113029.6A CN202010113029A CN111394448A CN 111394448 A CN111394448 A CN 111394448A CN 202010113029 A CN202010113029 A CN 202010113029A CN 111394448 A CN111394448 A CN 111394448A
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progranulin
gene
osteoporosis
product
protein
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李光飞
高焱
王爱飞
陈斌
蔚建鲁
徐又佳
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Second Affiliated Hospital of Soochow University
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Second Affiliated Hospital of Soochow University
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    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
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    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
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    • G01N2800/00—Detection or diagnosis of diseases
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    • G01N2800/108—Osteoporosis
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    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

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Abstract

The invention discloses application of Progranulin as a biomarker in preparation of a product for diagnosing postmenopausal osteoporosis, and belongs to the technical field of biological detection. The marker of the invention is Progranulin protein or gene. The invention discovers the correlation between the expression level of Progranulin protein or gene and postmenopausal osteoporosis for the first time, and can judge whether a subject suffers from osteoporosis or not or judge whether the subject has the risk of suffering from osteoporosis or not by detecting the expression of the Progranulin protein or gene in the bone tissue of postmenopausal women of the subject, so that the kit has timeliness, sensitivity and specificity; animal studies have shown that a decrease in Progranulin gene expression accelerates bone mass loss. The invention can make postmenopausal women know the osteoporosis risk in early stage, and prevent and treat high-risk patients in advance.

Description

Application of Progranulin as biomarker in preparation of product for diagnosing postmenopausal osteoporosis
Technical Field
The invention relates to application of Progranulin as a biomarker in preparation of a product for diagnosing postmenopausal osteoporosis, and belongs to the technical field of biological detection.
Background
Osteoporosis is a systemic bone disease characterized by decreased bone mass, microstructural damage of bone tissue, resulting in increased bone fragility and susceptibility to fracture (World Health Organization WHO, 1940). Osteoporosis can occur at any age, but is most common in postmenopausal women. Postmenopausal osteoporosis, also known as type I osteoporosis, is caused by an imbalance in bone resorption and bone remodeling due to a decrease in postmenopausal estrogen levels, resulting in thinning or fracture of trabecular bone, an increase in cortical bone pores, and ultimately a decrease in bone strength.
Osteoporosis is an age-related bone disease. At present, more than 21 hundred million people (about 15.5 percent of the total population) are aged over 60 years in China, nearly 14 hundred million people (about 10.1 percent of the total population) are aged over 65 years in China, and the aged people are the countries with the largest absolute number in the world. With the aging of population becoming more and more serious, osteoporosis becomes an important public health problem in China. Early epidemiological investigations showed that: the prevalence rate of osteoporosis of people over 50 years old in China is 20.7 percent for female and 14.4 percent for male; the prevalence rate of osteoporosis of people over 60 years old is obviously increased, and women are particularly prominent.
Osteoporotic fractures (or brittle fractures) refer to fractures that occur immediately upon minor trauma or daily activity and are a serious consequence of osteoporosis. The osteoporosis fracture has great harm, is one of the main causes of disability and death of old patients, particularly postmenopausal women, and often brings heavy burden to the society. Postmenopausal women also do not always have postmenopausal osteoporosis, so it would be of great significance if patients who may have postmenopausal osteoporosis in the future after menopause could be screened for early intervention and treatment.
Currently, the detection of postmenopausal osteoporosis includes the detection and auxiliary detection of laboratory indicators:
A. the bone formation markers include serum alkaline phosphatase (A L P), serum Osteocalcin (OC), serum I procollagen C-terminal propeptide (P1C-propeptide, P1CP), serum I procollagen N-terminal propeptide (P1N-propeptide, P1NP), and the bone absorption markers include serum I C-terminal cross-linked peptide (serum C-terminal peptide of collagen type 1), S-CTX phosphatase, serum anti-tartaric acid phosphatase (CP-phosphate), and urinary tract C-terminal cross-linked peptide (CP 1C-propeptide of collagen type).
B. Auxiliary inspection: including bone density measurement and bone imaging examination. Commonly used methods for bone density measurement are dual energy X-ray absorption measurement (DXA), Quantitative Computed Tomography (QCT), peripheral QCT (pQCT), and Quantitative Ultrasound (QUS). The bone imaging examination comprises thoracolumbar vertebra, hip, radius far-end and right-side X-ray films and the like.
However, the above method has the following drawbacks: laboratory detection indexes are as follows: the biochemical indexes of the bone transition markers are influenced by a plurality of factors, and the specificity of osteoporosis detection by using the biochemical indexes of the bone transition markers is not enough, and the prediction of postmenopausal osteoporosis is not good; auxiliary inspection: the general examination object is already the patient with the advanced osteoporosis, and is not suitable for screening the patient with the early postmenopausal osteoporosis.
Disclosure of Invention
Aiming at the problem that the traditional osteoporosis diagnosis method cannot realize early diagnosis and early prediction, the invention provides a molecular marker for early diagnosis of postmenopausal osteoporosis, and the molecular marker has timeliness, sensitivity and specificity, so that postmenopausal women can know the osteoporosis risk early, and prevention and treatment measures are taken in advance for high-risk patients.
The invention aims to provide application of Progranulin as a biomarker in preparing a product for diagnosing postmenopausal osteoporosis.
Further, the biomarker is Progranulin protein or gene.
Furthermore, the product is a product for diagnosing postmenopausal osteoporosis by detecting the expression level of Progranulin protein through immunodetection, protein chip detection or a high-throughput sequencing platform.
Further, the product for diagnosing postmenopausal osteoporosis by immunoassay of the expression level of the Progranulin protein comprises an antibody specifically binding to the Progranulin protein.
Further, the product for diagnosing postmenopausal osteoporosis by detecting the expression level of the Progranulin protein through the protein chip comprises an antibody specifically bound with the Progranulin protein.
Furthermore, the product is a product for diagnosing postmenopausal osteoporosis by detecting the expression of Progranulin genes through RT-PCR, real-time quantitative PCR, in-situ hybridization, a gene chip or a high-throughput sequencing platform.
Further, the product for diagnosing postmenopausal osteoporosis by detecting the expression of the Progranulin gene through RT-PCR at least comprises a pair of primers for specifically amplifying the Progranulin gene; the product for diagnosing postmenopausal osteoporosis by detecting the expression of the Progranulin gene through real-time quantitative PCR at least comprises a pair of primers for specifically amplifying the Progranulin gene.
Further, the product for diagnosing postmenopausal osteoporosis by detecting the expression of the Progranulin gene through in situ hybridization comprises a probe hybridized with the nucleotide sequence of the Progranulin gene.
Further, the product for diagnosing postmenopausal osteoporosis by detecting the expression of the Progranulin gene through the gene chip comprises a probe hybridized with the nucleotide sequence of the Progranulin gene.
The second purpose of the invention is to provide a kit, which comprises a reagent for detecting the expression level of Progranulin protein in bone tissues or peripheral blood.
The invention has the beneficial effects that:
the invention discovers the correlation between the expression level of Progranulin protein and postmenopausal osteoporosis for the first time, and can judge whether a subject suffers from osteoporosis or not or judge whether the subject has the risk of suffering from osteoporosis by detecting the expression of Progranulin protein in the bone tissue of the subject, so that the timeliness, the sensitivity and the specificity are realized, and postmenopausal women can know the risk of osteoporosis at an early stage and take prevention and treatment measures in advance for high-risk patients.
Drawings
FIG. 1 is a graph showing a comparison of the expression levels of Progranulin protein in bone tissues of three groups of patients with "normal bone mass", "reduced bone mass" and "osteoporosis";
FIG. 2 is a correlation analysis of femoral neck bone density values with bone tissue Progranulin expression levels;
FIG. 3 is a Micro-CT three-dimensional image comparison of WT and Progranulin-KO mouse femurs;
FIG. 4 is a Micro-CT two-dimensional image comparison of WT and Progranulin-KO mouse femurs;
FIG. 5 is a TRAP staining comparison of tibial bone tissue sections of WT and Progranulin-KO mice.
Detailed Description
The present invention is further described below in conjunction with the following figures and specific examples so that those skilled in the art may better understand the present invention and practice it, but the examples are not intended to limit the present invention.
Example 1: protein expression in bone tissue of postmenopausal women and correlation thereof with bone density
Materials: 65 postmenopausal female femoral neck fracture patients, bone densitometer, sps statistical software.
The method comprises the following steps: femoral neck fracture patients, inclusion criteria: menopausal women, unilateral femoral neck fracture, and joint replacement in need of hospitalization. Exclusion criteria: chronic liver and kidney diseases, metabolic diseases, tumors, blood system diseases, and patients who receive glucocorticoid, estrogen, calcitonin, bisphosphonate and the like for a long time. 65 patients were enrolled and signed an informed consent. In the course of joint replacement, a femoral head specimen on the affected side of a patient is collected and proteomics detection is carried out in cooperation with Hangzhou Jingjie biotechnology and science and technology Limited. Then, when the affected hip joint on the side of the patient is subjected to X-ray reexamination on the next day after the operation of the patient, the density detection of the bone on the neck of the femur (GE dual-energy X-ray bone densitometer) on the healthy side is carried out at the same time.
As a result: in proteomics results, it can be seen that there are many proteins expressed in bone tissues, and there are more than 80 proteins whose expression is abnormal in the groups of high bone density and low bone density. The invention focuses on the expression of the protein of the particle protein precursor (Progranulin) and the relation between the protein and the bone density, and is verified on animal experiments.
65 patients were classified into three groups of "normal bone mass", "reduced bone mass" and "osteoporosis" according to femoral neck bone density values. Proteomic results of three groups of patients the Progranulin protein levels were analyzed for ANOVA using SPSS software and were found to be statistically different between any two groups (P < 0.05). The above results indicate that the expression level of bone tissue Progranulin protein was decreased in the "decreased bone mass" group compared with the "normal bone mass" group, and that the expression level of bone tissue Progranulin protein was further decreased in the "osteoporosis" group compared with the "decreased bone mass" group (fig. 1).
Femoral neck bone density values and bone tissue Progranulin levels were correlated for 65 patients using SPSS software. The results show that the expression level of the bone tissue Progranulin is correlated with the femoral neck bone density value, namely the higher the expression level of the bone tissue Progranulin is, the higher the bone density value is; i.e. the lower the expression level of bone tissue Progranulin, the lower the bone density values (fig. 2).
Example 2: demonstration of a decrease in Progranulin gene expression after castration at the animal level accelerates bone mass loss
Materials 2 months old wild type mice (WT) and Progranulin knock-out mice (Progranulin-KO), both wild type mice (WT) and Progranulin knock-out mice (Progranulin-KO) were obtained from Jackson laboratories (the Jackson L absorber).
The method comprises the following steps: wild-type mice (WT) and Progranulin knockout mice (Progranulin-KO) at 2 months of age were taken, Ovariectomy (OVX) was performed to prepare an animal model of postmenopausal osteoporosis, and then the mice were sacrificed 3 weeks later, and a femoral sample of the mice was taken for Micro-CT detection. Mouse tibia specimen is decalcified, embedded in paraffin, sliced and TRAP stained.
As a result: Micro-CT detection three-dimensional images show that the bone mass of a castrated osteoporosis model mouse after the gene of Progranulin is knocked out is obviously reduced compared with that of a wild type mouse, and the bone mass is equivalent to that of postmenopausal osteoporosis women, and if the gene of Progranulin in vivo is deficient, osteoporosis is easily caused (figure 3); Micro-CT detection two-dimensional images show that the number of trabeculae of a mouse with castration osteoporosis after the gene of Progranulin is knocked out is obviously reduced compared with that of a wild type mouse, and the mouse is equivalent to a postmenopausal osteoporosis woman, and if the gene of Progranulin in vivo is deficient, bone formation is easy to reduce (figure 4); TRAP staining results of bone tissue sections show that the number of osteoclasts in mice of a castration osteoporosis model after the Progranulin gene knockout is obviously increased compared with that in wild-type mice, and the mice are equivalent to postmenopausal osteoporosis women, and if the Progranulin gene in vivo is deficient, the bone resorption is easily increased (figure 5).
The above-mentioned embodiments are merely preferred embodiments for fully illustrating the present invention, and the scope of the present invention is not limited thereto. The equivalent substitution or change made by the technical personnel in the technical field on the basis of the invention is all within the protection scope of the invention. The protection scope of the invention is subject to the claims.

Claims (10)

  1. Application of Progranulin as a biomarker in preparation of products for diagnosing postmenopausal osteoporosis.
  2. 2. The use of claim 1, wherein the biomarker is a Progranulin protein or gene.
  3. 3. The use according to claim 2, wherein the product is a product for diagnosing postmenopausal osteoporosis by detecting the expression level of Progranulin protein through immunodetection, protein chip detection or high throughput sequencing platform.
  4. 4. The use according to claim 3, wherein the product for diagnosing postmenopausal osteoporosis by immunodetection of the expression level of Progranulin protein comprises an antibody specifically binding to Progranulin protein.
  5. 5. The use according to claim 3, wherein the product for diagnosing postmenopausal osteoporosis by detecting the expression level of Progranulin protein through a protein chip comprises an antibody specifically binding to Progranulin protein.
  6. 6. The use according to claim 2, wherein the product is a product for diagnosing postmenopausal osteoporosis by detecting Progranulin gene expression by RT-PCR, real-time quantitative PCR, in situ hybridization, gene chip, or high throughput sequencing platform.
  7. 7. The use according to claim 6, wherein the product for diagnosing postmenopausal osteoporosis by detecting the expression of Progranulin gene through RT-PCR comprises at least one pair of primers for specifically amplifying the Progranulin gene; the product for diagnosing postmenopausal osteoporosis by detecting the expression of the Progranulin gene through real-time quantitative PCR at least comprises a pair of primers for specifically amplifying the Progranulin gene.
  8. 8. The use according to claim 6, wherein the product for diagnosing postmenopausal osteoporosis by detecting the expression of the Progranulin gene by in situ hybridization comprises a probe that hybridizes to a nucleotide sequence of the Progranulin gene.
  9. 9. The use according to claim 6, wherein the product for diagnosing postmenopausal osteoporosis by detecting the expression of Progranulin gene through a gene chip comprises a probe that hybridizes with a nucleotide sequence of Progranulin gene.
  10. 10. A kit comprising a reagent for detecting the expression level of Progranulin protein in bone tissue or peripheral blood.
CN202010113029.6A 2020-02-24 2020-02-24 Application of Progranulin as biomarker in preparation of product for diagnosing postmenopausal osteoporosis Pending CN111394448A (en)

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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160319286A1 (en) * 2013-10-15 2016-11-03 Osteoneurogen Composition for preventing or treating osteoporosis, containing progranulin inhibitor as active ingredient
CN107164507A (en) * 2017-06-16 2017-09-15 首都医科大学附属北京友谊医院 The diagnostic tool of postmenopausal women's primary osteoporosis

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20160319286A1 (en) * 2013-10-15 2016-11-03 Osteoneurogen Composition for preventing or treating osteoporosis, containing progranulin inhibitor as active ingredient
CN107164507A (en) * 2017-06-16 2017-09-15 首都医科大学附属北京友谊医院 The diagnostic tool of postmenopausal women's primary osteoporosis

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
唐伟: "生长因子Progranulin结合肿瘤坏死因子受体家族成员及其在自身免疫性疾病中的功能研究", 《中国博士学位论文全文数据库 医药卫生科技辑》 *

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