CN-122005583-A - Application of cPLA2 inhibitor in preparation of osteoporosis treatment medicine

Abstract

The invention relates to an application of a cPLA2 inhibitor in preparing a medicament for treating osteoporosis, belonging to the technical field of biomedical research. The invention confirms that cPLA2 plays a key role in the pathological process of osteoporosis through in vitro and in vivo experiments, specifically, cPLA2 is positively correlated with the up-regulation of osteoclast related genes (ACP 5, CTSK, cFOS, MMP, DC-stamp) and inflammatory factors (IL-6, IL-1 beta, TNF-a) in the occurrence process of osteoporosis, cPLA2 plays a key role in the inflammation of osteoporosis, and reduces the secondary pathological change of the osteoporosis through targeted inhibition of the expression of the cPLA2, and the discovery provides a new target point for the treatment of the osteoporosis. The invention screens out small molecular compound martin which can be used for treating osteoporosis by taking cPLA2 as a target point.

Inventors

• LIU RONGHAN
• NING BIN
• Niu Jiayao
• LI ZHENG
• JIANG WEI
• ZHANG YING
• KANG JIANNING
• ZOU YUNPENG
• WANG ZHIPENG
• ZHANG ZHIYUAN

Assignees

• 济南市中心医院

Dates

Publication Date

20260512

Application Date

20260114

Priority Date

20250114

Claims (9)

1. 1. Use of a cPLA2 inhibitor in the manufacture of a medicament for the treatment of osteoporosis.
2. 2. The use according to claim 1, wherein the cPLA2 inhibitor is capable of achieving the effect of treating osteoporosis by reducing the expression level of cPLA2 or reducing the protein activity of cPLA2, increasing bone density and compression resistance, reducing the expression level of an osteoclast-associated gene and inflammatory factors, and thereby alleviating the onset of osteoporosis.
3. 3. The use of claim 1, wherein the cPLA2 inhibitor is capable of achieving an effect of treating osteoporosis by decreasing the expression level of cPLA2 or decreasing the protein activity of cPLA2, increasing bone density, decreasing the expression level of inflammatory factors, and thereby alleviating osteolysis.
4. 4. The use according to claim 1, wherein the cPLA2 inhibitor is capable of achieving an effect of treating osteoporosis by reducing the expression level of cPLA2 or reducing the protein activity of cPLA2, inhibiting the effect of RANKL, preventing osteoclast differentiation.
5. 5. The use of claim 1, wherein the cPLA2 inhibitor comprises marlin.
6. 6. The application of cPLA2 as a target spot in screening osteoporosis therapeutic drugs.
7. 7. The use of claim 6, wherein the selected osteoporosis therapeutic agent targets cPLA2 to reduce the expression level of cPLA2 or reduce the protein activity of cPLA 2.
8. 8. The use of claim 6, wherein the selected osteoporosis therapeutic agent targets cPLA2, and wherein the agent binds to cPLA2 to increase the stability of the cPLA2 protein.
9. 9. The use of claim 6, wherein the osteoporosis treatment agent comprises martin.

Description

Application of cPLA2 inhibitor in preparation of osteoporosis treatment medicine Technical Field The invention relates to an application of a cPLA2 inhibitor in preparing a medicament for treating osteoporosis, belonging to the technical field of biomedical research. Background Osteoporosis is a systemic chronic inflammatory disease that is caused by a disturbance in the balance of bone resorption and bone formation, and is manifested by a decrease in bone mass, a decrease in bone density, and a tendency to fracture. With the further development of the aging social process, the number of patients with osteoporosis is suddenly increased, and the osteoporosis gradually "gnaws" our health, and simultaneously, great burden is brought to families and society. The clinical application at the present stage can not realize comprehensive and effective intervention, and is difficult to truly regulate and control bone metabolism balance. Therefore, prevention and treatment of osteoporosis has become a difficult problem to be solved in the medical community. Bone is a tissue with high metabolic activity, and is subjected to bone remodeling and bone turnover at any time, and the process is mainly realized through bone formation regulated by osteoblasts and bone resorption regulated by osteoclasts. RANK/RANKL/OPG is an important signal mediating the balance of bone resorption and bone formation and is critical for maintaining the balance of bone metabolism. RANKL is an essential factor for osteoclast differentiation, is secreted by bone cells, preosteoblasts or immune cells, binds to RANK on the cell surface of an osteoclast precursor, activates NF- κb transcription factors, increases the transcription and translation levels of osteoclast differentiation related genes c-FOS, NFATc1, promotes fusion into polynuclear cells and activation into mature osteoclasts, secretes hydrochloric acid and various hydrolytic enzymes to dissolve minerals, and reduces bone matrix. The osteoclast inhibitor (OPG) plays a role in inhibiting osteoclast differentiation by binding to RANKL and competitively inhibiting the RANKL-RANK system. Therefore, the current research and drug development focus is on how to inhibit RANKL function. At present, the clinically common medicines mainly comprise zoledronic acid and Deshu monoclonal antibody, but the clinically common medicines have larger limitations on clinical application and prevention and control effects. Zoledronic acid can be combined with osteoclasts to inhibit the functions of the osteoclasts and reduce bone loss, but has great side effects, can cause fever, hypocalcemia, gastrointestinal tract reaction, kidney function damage and the like, and cannot realize long-time effective intervention of medicines. The Deshu monoclonal antibody is a monoclonal antibody of RANKL, has stronger targeting property, can effectively bind to the RANKL, prevent the RANKL from activating the RANK on the surfaces of osteoclasts and precursor cells thereof, inhibit the maturation and activation of the osteoclasts and reduce bone loss, but has stronger withdrawal reaction, and enhances the quantity and activity rebound of the osteoclasts after the Deshu monoclonal antibody stops, thereby causing rapid bone mass loss and being extremely easy to cause recurrent fracture. In domestic and foreign researches, the regulation and control of the RANKL signal is an intricate and complex process in the occurrence and development process of osteoporosis, wherein inflammatory reaction, oxidative stress, lipid metabolism, autophagy injury and the like can lead to the increase of bone loss induced by the RANKL, and the RANKL can also aggravate the pathological process and aggravate the bone loss speed. The RANKL signal network cannot be comprehensively inhibited by single factor regulation, so that searching for an important target point capable of realizing comprehensive regulation in the osteoporosis onset process is a key scientific problem. To achieve targeted, comprehensive regulation of bone metabolism, we have found, through transcriptome and proteome combinatorial analysis, that phospholipase A2 (cPLA 2/PLA2G 4A) plays a key role in bone metabolism regulation. cPLA2 is a widely distributed enzyme which can participate in various cellular reactions, such as cell proliferation, differentiation, inflammation and the like, and amino acid 505 of the cPLA2 can be activated by extracellular regulatory kinase 1/2 (ERK 1/2) and p38 mitogen activated protein kinase (p 38 MAPK) phosphorylation, and the activated cPLA2 can play roles in1 degrading phospholipids on the surface of lysosomes, causing lysosome damage, inhibiting fusion with autophagosomes, blocking autophagy flow, 2 catalyzing hydrolysis of glycerolipids to generate lysophospholipids and releasing Arachidonic Acid (AA), causing lipid metabolism disorder, 3, generating phosphorylation, transmitting inflammatory signals, and further exacerbating inflammatory reaction