Tristetraprolin Upregulation Reduces Frailty and Increases Bone Density in Old Mice
Researchers here report that life-long tristetraprolin (TTP) upregulation leads to reduced frailty and improved bone mineral density in aged mice. One of the functions of TTP is that it suppresses expression of the pro-inflammatory TNF-α cytokine, so a reduced degree of age-related inflammation would be the first place to look for an explanation of the outcome noted here. It is an open question as to whether TTP upregulation produces a more nuanced and reactive reduction of TNF-α signaling than is the case for the blunt, across the board inhibition achieved by present anti-TNF-α therapies, and is thus a mechanism that interferes less in the necessary immune response to injury and infection.
Researchers have presented results from a study aiming to use a novel transgenic mouse model (TTP knock-in - TTPKI) that has a moderate elevation of tristetraprolin (TTP) systemically to understand if there is a long-term benefit for bone health. The study performed body composition, physical performance assessments, and frailty assessments on the 6-month-old and 22-month-old TTPKI and C57BL/6N wild-type male and female mice.
Microcomputed tomography (µCT) and decalcified sections of the tibia were used to determine static bone histomorphometric parameters and bone histomorphometry, respectively. Immunophenotypic analysis of bone marrow (BM), spleen, and mesenteric lymph nodes were analyzed by flow cytometry for myeloid and lymphocyte populations. Myeloid population BM osteoclastogenic potential was assessed.
Body composition with aged control and TTPKI mice revealed significant sex and genotype differences. Aged TTPKI mice displayed decreased frailty scores and increased quality of life compared to control similarly aged mice. The tibia from aged TTPKI mice exhibited higher bone mineral density (BMD) than aged control mice. Age-related decline in immune cell composition was partially reversed in aged TTPKI mice. In an osteoclast differentiation assay, BM myeloid progenitors from TTPKI mice exhibited fewer osteoclasts with reduced eroded bone surface area. Improved functional capacity, BMD, and immune cell composition indicate that enhanced expression of TTP can promote a healthier phenotype during aging.