CD4(+) T-cell activation of bone marrow causes bone fragility and insulin resistance in type 2 diabetes
Por:
Cifuentes-Mendiola, S. E., Solis-Suarez, D. L., Martinez-Davalos, A., Godinez-Victoria, M., Garcia-Hernandez, A. L.
Publicada:
1 feb 2022
Resumen:
Type 2 diabetes mellitus (T2DM) causes an increased risk of bone
fractures. However, the pathophysiology of diabetic bone fragility is
not completely understood. It has been proposed that an inflammatory
microenvironment in bone could be a major mechanism by inducing
uncontrolled bone resorption, inadequate bone formation and consequently
more porous bones. We propose that activated T-cells in the bone marrow
cause a proinflammatory microenvironment in bone, and cause bone
fragility in T2DM. We induced T2DM in C57BL/6 male mice through a
hypercaloric diet rich in carbohydrates and low doses of streptozocin.
In T2DM mice we inhibited systemic activation of T-cells with a fusion
protein between the extracellular domain of Cytotoxic T-Lymphocyte
Antigen 4 and the Fc domain of human immunoglobulin G (CTLA4-Ig). We
analysed the effects of T2DM or CTLA4-Ig in lymphocyte cell subsets and
antigen-presenting cells in peripheral blood and femoral bone marrow;
and their effect on the metabolic phenotype, blood and bone cytokine
concentration, femoral bone microarchitecture and biomechanical
properties, and the number of osteoblast-like cells in the femoral
endosteum. We performed a Pearson multiple correlation analysis between
all variables in order to understand the global mechanism. Results
demonstrated that CTLA4-Ig decreased the number of activated CD4(+)
T-cells in the femoral bone marrow and consequently decreased TNF-alpha
and RANK-L concentration in bone, notably improved femoral bone
microarchitecture and biomechanical properties, increased the number of
osteoblast-like cells, and reduces osteoclastic activity compared to
T2DM mice that did not receive the inhibitor. Interestingly, we observed
that blood glucose levels and insulin resistance may be related to the
increase in activated CD4(+) T-cells in the bone marrow. We conclude
that bone marrow activated CD4(+) T-cells cause poor bone quality and
insulin resistance in T2DM.
Filiaciones:
Laboratory of Dental Research, Section of Osteoimmunology and Oral Immunology, FES Iztacala, National Autonomous University of Mexico, A. Jiménez Gallardo SN, San Sebastián Xhala, Cuautitlán Izcalli, Estado de México CP 54714, Mexico
Postgraduate in Biological Sciences, National Autonomous University of Mexico, Mexico, Mexico
Physics Institute, National Autonomous University of Mexico, Circuito de la Investigación Científica, Ciudad Universitaria, México City, 04510, Mexico
Sección de Estudios de Posgrado e Investigación, Escuela Superior de Medicina, Instituto Politécnico Nacional, Mexico, Mexico
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