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Application of fibroblast activation protein (Fap) as drug target in treatment of osteoarthritis (OA)

A fibroblast and activating protein technology, used in the treatment of osteoarthritis, fibroblast activating protein as a drug target, fibroblast activating protein field, can solve problems such as poor effect

Pending Publication Date: 2021-03-19
SHANGHAI EAST HOSPITAL EAST HOSPITAL TONGJI UNIV SCHOOL OF MEDICINE
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] Aiming at the above-mentioned technical problems in the prior art, the present invention provides the use of fibroblast activating protein as a drug target in the treatment of osteoarthritis, the fibroblast activating protein as a drug target in the treatment of osteoarthritis The use in inflammation will solve the technical problem that the drugs in the prior art are not effective in treating osteoarthritis or inhibiting cartilage damage or osteophyte formation or synovial inflammation

Method used

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  • Application of fibroblast activation protein (Fap) as drug target in treatment of osteoarthritis (OA)
  • Application of fibroblast activation protein (Fap) as drug target in treatment of osteoarthritis (OA)
  • Application of fibroblast activation protein (Fap) as drug target in treatment of osteoarthritis (OA)

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1 Fap is up-regulated in OA synovium

[0042] In this example, the expression of Fap in synovial tissue was determined by immunofluorescence, qRT-PCR and Western blotting.

[0043] The synovial membranes of the control group (non-OA acute injury) and OA patients were collected, fixed and dehydrated, and frozen sectioned. The expression of Fap in the synovial tissue was detected by immunofluorescence experiment, and it was found that the expression of Fap in the synovial tissue of the control group was very low. low, while Fap was highly expressed in the synovial tissue of OA patients ( figure 1 A).

[0044] The synovium of the control group and OA patients was collected, and the expression of Fap in the synovium was detected by qRT-PCR and Western blot experiments. It was found that the results were consistent with the results of immunofluorescence. The mRNA and protein levels of Fap in the synovial tissue of OA patients were significantly higher than Synovial...

Embodiment 2

[0046] Example 2 Genetic and pharmacological inhibition of Fap alleviates the progression of OA in mice

[0047] In order to study whether Fap regulates the progression of OA, we constructed a DMM model to simulate OA in wild-type and Fap knockout mice, and injected Fap-specific small molecule inhibitors into the knee joint cavity every week on the third day after surgery. or vehicle control (PBS). After modeling, wild-type mice showed significant cartilage erosion, osteophyte formation, and synovial inflammation. On the one hand, cartilage erosion and synovial inflammation were significantly reduced in Fap knockout mice, while osteophyte formation tended to be reduced. On the one hand, wild-type mice injected with Fap inhibitors in the joint cavity also showed significantly reduced cartilage erosion, osteophyte formation, and synovial inflammation ( figure 2 A-F). Intra-articular injection of Fap inhibitor (Ac-Gly-BoroPro) has no therapeutic effect on Fap knockout mice, su...

Embodiment 3

[0048] Example 3 Intra-articular injection of Fap inhibitor has therapeutic effect on OA in mice

[0049] In order to test whether the Fap inhibitor (Ac-Gly-BoroPro) can alleviate the joint symptoms of OA after the onset of OA, we injected the Fap inhibitor (Ac-Gly-BoroPro) into the knee joint cavity of the mice after 4 weeks of DMM every week. -BoroPro) or vehicle control (PBS). After 8 weeks of injection, the vehicle control group had obvious cartilage erosion, osteophyte formation and synovial inflammation compared with the sham operation group, while the OA in the Fap inhibitor group was significantly reduced ( image 3 A-F). Immunofluorescence experiments of aggrecan proved that Fap inhibitor (Ac-Gly-BoroPro) can alleviate the loss of aggrecan in articular cartilage ( image 3 G, H).

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Abstract

The invention provides application of fibroblast activation protein (Fap) as a target in screening drugs for treating osteoarthritis (OA) or inhibiting cartilage injury or osteophyte generation or synovitis. The invention also provides application of an Fap gene as a target in screening drugs for treating OA or inhibiting cartilage injury or osteophyte generation or synovitis. The invention also provides application of a targeted Fap inhibitor in preparation of drugs for treating OA or inhibiting cartilage injury or osteophyte generation or synovitis. The invention also provides application ofosteolectin (Oln) in preparation of drugs for treating OA or inhibiting cartilage injury or osteophyte generation or synovitis. It is found that Fap is highly expressed in synovial membrane of OA, cartilage injury, osteophyte generation, synovitis and cartilage aggregation protein polysaccharide loss of mouse OA can be relieved by inhibiting Fap through genetics and pharmacology, and both an Fapsmall-molecule inhibitor and an endogenous protein inhibitor Oln can treat the OA.

Description

technical field [0001] The invention belongs to the field of biotechnology, and relates to a fibroblast activation protein, specifically the use of the fibroblast activation protein as a drug target in the treatment of osteoarthritis. Background technique [0002] Osteoarthritis (OA) is one of the most common orthopedic diseases, and the prevalence of OA in people over 45 years old is as high as 26%. The main pathological changes in OA are degeneration of articular cartilage, combined with osteophyte formation, low level of inflammation and subchondral bone remodeling. The mechanical wear of articular cartilage at the initial stage of OA will promote the secretion of various pro-inflammatory factors and matrix-degrading enzymes in tissues such as cartilage and synovium, which will further aggravate the degradation of cartilage matrix. Early OA can be treated by microfracture, osteochondral mosaic plastic surgery and autologous cartilage transplantation, but the efficacy i...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C12Q1/6883G01N33/68A61K38/18A61K45/06A61P19/02A61P19/04A61P19/08
CPCC12Q1/6883G01N33/6893A61K45/06A61K38/1875A61P19/02A61P19/04A61P19/08C12Q2600/158G01N2800/105
Inventor 岳锐尹峰范骜元
Owner SHANGHAI EAST HOSPITAL EAST HOSPITAL TONGJI UNIV SCHOOL OF MEDICINE
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