PMID- 34896656
OWN - NLM
STAT- MEDLINE
DCOM- 20220418
LR  - 20220418
IS  - 1873-2763 (Electronic)
IS  - 1873-2763 (Linking)
VI  - 155
DP  - 2022 Feb
TI  - CD4(+) T-cell activation of bone marrow causes bone fragility and insulin 
      resistance in type 2 diabetes.
PG  - 116292
LID - S8756-3282(21)00458-0 [pii]
LID - 10.1016/j.bone.2021.116292 [doi]
AB  - 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 pro-inflammatory 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.
CI  - Published by Elsevier Inc.
FAU - Cifuentes-Mendiola, S E
AU  - Cifuentes-Mendiola SE
AD  - Laboratory of Dental Research, Section of Osteoimmunology and Oral Immunology, 
      FES Iztacala, National Autonomous University of Mexico, A. Jimenez Gallardo SN, 
      San Sebastian Xhala, Cuautitlan Izcalli, Estado de Mexico, CP 54714, Mexico; 
      Postgraduate in Biological Sciences, National Autonomous University of Mexico, 
      Mexico, Mexico.
FAU - Solis-Suarez, D L
AU  - Solis-Suarez DL
AD  - Laboratory of Dental Research, Section of Osteoimmunology and Oral Immunology, 
      FES Iztacala, National Autonomous University of Mexico, A. Jimenez Gallardo SN, 
      San Sebastian Xhala, Cuautitlan Izcalli, Estado de Mexico, CP 54714, Mexico.
FAU - Martinez-Davalos, A
AU  - Martinez-Davalos A
AD  - Physics Institute, National Autonomous University of Mexico, Circuito de la 
      Investigacion Cientifica, Ciudad Universitaria, 04510 Mexico City, Mexico.
FAU - Godinez-Victoria, M
AU  - Godinez-Victoria M
AD  - Seccion de Estudios de Posgrado e Investigacion, Escuela Superior de Medicina, 
      Instituto Politecnico Nacional, Mexico, Mexico.
FAU - Garcia-Hernandez, A L
AU  - Garcia-Hernandez AL
AD  - Laboratory of Dental Research, Section of Osteoimmunology and Oral Immunology, 
      FES Iztacala, National Autonomous University of Mexico, A. Jimenez Gallardo SN, 
      San Sebastian Xhala, Cuautitlan Izcalli, Estado de Mexico, CP 54714, Mexico. 
      Electronic address: ana.garcia@unam.mx.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20211209
PL  - United States
TA  - Bone
JT  - Bone
JID - 8504048
RN  - 7D0YB67S97 (Abatacept)
SB  - IM
MH  - Abatacept/metabolism
MH  - Animals
MH  - Bone Marrow/metabolism
MH  - CD4-Positive T-Lymphocytes
MH  - *Diabetes Mellitus, Type 2/complications/metabolism
MH  - Female
MH  - *Insulin Resistance
MH  - Male
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - T-Lymphocytes/metabolism
OTO - NOTNLM
OT  - Activated T-cells
OT  - Bone fragility
OT  - Bone marrow
OT  - Bone quality
OT  - Type 2 diabetes
EDAT- 2021/12/14 06:00
MHDA- 2022/04/19 06:00
CRDT- 2021/12/13 12:25
PHST- 2021/10/21 00:00 [received]
PHST- 2021/12/02 00:00 [revised]
PHST- 2021/12/03 00:00 [accepted]
PHST- 2021/12/14 06:00 [pubmed]
PHST- 2022/04/19 06:00 [medline]
PHST- 2021/12/13 12:25 [entrez]
AID - S8756-3282(21)00458-0 [pii]
AID - 10.1016/j.bone.2021.116292 [doi]
PST - ppublish
SO  - Bone. 2022 Feb;155:116292. doi: 10.1016/j.bone.2021.116292. Epub 2021 Dec 9.