Researchers from Nankai University, Rush University, and the Chinese Academy of Medical Sciences have confirmed in new research that AKT protein plays a vital role in the formation of osteoclasts and osteolysis induced by myeloma. The research results were published in the Journal of Biochemistry (JBC).
Professor Guozhi Xiao of the School of Life Sciences of Nankai University is the corresponding author of this paper. He has been devoted to the research of bone biology for many years, and has a profound knowledge in the differentiation and maturation of osteoblasts. Published more than 40 papers in major academic journals such as biochemistry, immunology, and endocrinology. He is also serving as a lecturer professor in the Department of Biochemistry at Rush University.
Multiple myeloma (MM) is a malignant disease of bone marrow plasma cells. In the United States, the incidence rate is 3 / 100,000, surpassing leukemia, second only to lymphoma, ranking second in hematological malignancies. The incidence rate in Asia is 1 in 100,000, and there is no complete statistical data in China, which is estimated to be about 1 in 100,000. Multiple myeloma occurs mostly in middle-aged and elderly people between 40 and 70 years old. With the continuous growth of the life expectancy of our population, the incidence of multiple myeloma gradually increases.
Multiple myeloma is caused by the malignant transformation of plasma cells with synthetic and secreted immunoglobulins, and the proliferation of a large number of monoclonal malignant plasma cells. Most tumors invade bone and bone marrow, resulting in osteolytic lesions. Abnormal osteoclast formation and osteolysis are hallmarks of multiple myeloma bone disease, but the underlying molecular mechanism is not yet clear.
In this article, the researchers confirmed that the AKT signaling pathway is upregulated in primary bone marrow mononuclear cells (BMM) from patients with multiple myeloma, resulting in the receptor activator (NF-κB receptor activator) in osteoclast precursor cells. of NF-κB, RANK) continued to be highly expressed. Inhibition of AKT in primary bone marrow mononuclear cell culture in patients with multiple myeloma can block RANK up-regulation and osteoclast formation. When the researchers used conditioned medium from multiple myeloma cell cultures to grow primary bone marrow mononuclear cell cultures, it was confirmed that they can activate the latter's AKT, increase RANK expression, and promote osteoclast formation. Inhibiting AKT in cultured multiple myeloma cells can slow their growth and promote osteoclast-forming ability.
Clinically, the researchers confirmed that systemic administration of the AKT inhibitor LY294002 can block the formation of tumor tissue in the bone marrow cavity of severe combined immunodeficiency mice (SCID mice), destroying the formation of multiple myeloma-induced osteoclasts and Osteolysis. They found that ATF4 levels in primary bone marrow mononuclear cell cultures from patients with multiple myeloma were upregulated. Adenovirus-mediated ATF4 overexpression in osteoclast precursor cells activated RANK expression.
These results confirm that AKT plays an important role in the osteoclastogenesis and osteolysis induced by multiple myeloma, at least in part through ATF4-dependent up-regulation of RANK expression in osteoclast precursor cells.
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