CN-122005560-A - Use of OGG1 inhibitors for the treatment of bone defects with impaired osteogenic differentiation

Abstract

The application belongs to the technical field of biology, and particularly relates to application of an OGG1 inhibitor in treating bone defects with osteogenic differentiation disorders. Mainly provides the application of the OGG1 inhibitor in preparing medicines for treating bone defects with osteogenic differentiation disorder. Compared with the existing osteogenesis promoting drugs, the application introduces the OGG1 specific small molecule inhibitor TH5487 as a candidate drug for treating the osteogenesis disturbance bone defect, has the advantages of clear target point and clear action mechanism, can release the negative regulation and control of the osteogenesis by inhibiting the activity of the OGG1, thereby realizing the accurate intervention of the bone formation process, providing theoretical basis and technical scheme for the application of the OGG1 gene/protein and the inhibitor thereof in the bone formation related diseases, and has good clinical transformation potential and application prospect.

Inventors

• ZHANG BIN
• HU JIAWEI
• KUANG ZHIHUI
• ZHONG YANLONG

Assignees

• 南昌大学

Dates

Publication Date

20260512

Application Date

20260415

Claims (5)

1. Use of an OGG1 inhibitor for the manufacture of a medicament for the treatment of bone defects with dysosteogenic differentiation, characterized in that said OGG1 inhibitor is TH5487.
2. 2. The use according to claim 1, wherein the osteogenic differentiation-impaired bone defect comprises a traumatic bone defect, a bone fracture nonunion/delayed healing with bone defect, a bone defect resulting from oxidative stress-related bone formation disorder.
3. 3. The use according to claim 1, wherein the pharmaceutical dosage form is any one of an oral formulation, an injection or a sustained release formulation.
4. Application of OGG1 gene and/or OGG1 protein as target in screening of medicines for treating bone defect due to osteogenic differentiation disorder.
5. 5. Application of a reagent for detecting OGG1 gene and/or OGG1 protein expression in preparation of bone defect diagnosis and/or prognosis products for bone differentiation disorder.

Description

Use of OGG1 inhibitors for the treatment of bone defects with impaired osteogenic differentiation Technical Field The application belongs to the technical field of biology, and particularly relates to application of an OGG1 inhibitor in treating bone defects with osteogenic differentiation disorders. Background The bone defect is a bone regeneration failure disease caused by a plurality of pathological factors such as wound, aging, inflammatory reaction, oxidative stress and the like, and the core pathological basis is that bone mesenchymal stem cells are inhibited in bone differentiation capacity, so that the bone defect is not healed for a long time and even the bone structure and function are seriously damaged due to insufficient new bone generation. With the acceleration of the aging process of population and the continuous rising of the incidence rate of traumatic bone injury, bone defects related to osteogenic differentiation disorder have become an important treatment problem facing the clinical orthopedics and regenerative medicine fields. The main means for clinically treating bone defects at present comprise bone grafting, bone substitute material implantation, osteogenesis promoting drug application and the like, but the methods are focused on providing mechanical support or exogenous stimulation, are difficult to correct the internal mechanism of continuous suppression of osteogenic differentiation under pathological conditions from molecular level, and have still no ideal treatment effect in senile bone defects, complex traumatic bone defects and disease states accompanied by significant oxidative stress environments. Therefore, the new molecular targets are searched and targeted therapeutic drugs aiming at osteogenic differentiation disorders are developed, and the method has important clinical demands and application values. Disclosure of Invention The invention aims to solve the defects of the prior art, aims to solve the problems that the existing treatment means of bone defects and osteogenic differentiation disorders mainly depend on structural repair or exogenous osteogenic stimulation and lack a definite targeted intervention strategy aiming at key molecular mechanisms of osteogenic differentiation inhibition under pathological conditions, provides a drug application which takes OGG1 genes/proteins and inhibitors thereof as action targets and can be used for treating the osteogenic differentiation disorder bone defects, and particularly provides an application of an OGG1 inhibitor in treating the osteogenic differentiation disorder bone defects, and adopts the following technical scheme: in a first aspect, the invention provides the use of an OGG1 inhibitor in the manufacture of a medicament for the treatment of bone defects with dysosteogenic differentiation, said OGG1 inhibitor TH5487. OGG1 specific small molecule inhibitor TH5487 is used for preparing medicine for treating bone defect of osteogenic differentiation disorder, the TH5487 can promote osteogenic differentiation of BMSCs and up-regulate osteogenic related markers (Col 1a1, runx2, OCN), and ALP and ARS indexes are enhanced. 8-Hydroxyguanine DNA glycosidase 1 (8-oxoguanine DNA glycosylase 1, OGG 1) is activated under oxidative stress conditions as a key DNA base excision repair enzyme. However, the bone formation activity under pathological conditions is very complex, and the experimental study shows that abnormal activation of OGG1 under pathological conditions can be used as a negative regulatory factor of bone formation differentiation, inhibit the expression of bone formation related genes, reduce the bone formation differentiation capacity of bone marrow mesenchymal stem cells, and further prevent bone formation and bone defect repair. Further research shows that the inhibition or knocking out of OGG1 can obviously enhance the osteogenic differentiation potential of bone marrow mesenchymal stem cells, and quicken the repair process of bone defect in an in vivo model, thereby prompting that OGG1 has important pharmaceutical intervention value in bone defect with osteogenic differentiation disorder. The medicine can be used for treating or promoting bone defect regeneration under pathological conditions by regulating and controlling the expression level or activity of OGG1 gene or protein, and can promote the osteogenic differentiation level of mesenchymal stem cells by inhibiting the expression of OGG1 gene so as to interfere with the pathological process of bone defect. As a further preferred embodiment, the bone defect with impaired osteogenic differentiation includes traumatic bone defect, bone defect accompanied by bone defect with delayed fracture healing, and bone defect caused by oxidative stress related bone formation disorder. As a further preferred embodiment, the pharmaceutical dosage form is any one of an oral preparation, an injection or a sustained release preparation. In a second aspect, the invention prov