PMID- 32603908
OWN - NLM
STAT- MEDLINE
DCOM- 20210617
LR  - 20210617
IS  - 1873-2763 (Electronic)
IS  - 1873-2763 (Linking)
VI  - 138
DP  - 2020 Sep
TI  - Zoledronate decreases CTLA-4 in vivo and in vitro independently of its action on 
      bone resorption.
PG  - 115512
LID - S8756-3282(20)30292-1 [pii]
LID - 10.1016/j.bone.2020.115512 [doi]
AB  - Acute phase response (APR) following intravenous zoledronate (ZOL) administration 
      is related to activation and increased proliferation of gammadelta T cells, attributed to 
      the molecular mechanism of action of nitrogen-containing bisphosphonates (N-BPs). 
      ZOL, however, has also been reported to inhibit the proliferation of regulatory T 
      cells in vitro and to reduce the expression of Cytotoxic T-Lymphocyte Antigen-4 
      (CTLA-4), a negative regulator of T cell activation that is increased in patients 
      with autoimmune diseases. There are, however, no data on the relationship between 
      ZOL treatment and soluble(s)CTLA-4 either in vivo in relevant patient populations 
      or in vitro with the use of assays relevant to the mechanism of action of N-BPs. 
      The objectives of the present study were firstly, to characterize the ZOL-induced 
      APR in patients with inflammatory rheumatic diseases (IRDs) and its relationship 
      with changes in circulating sCTLA-4 and secondly, to investigate the effects of 
      ZOL on CTLA-4 production and expression by peripheral blood mononuclear cells 
      (PBMCs). We studied 10 postmenopausal women with IRDs treated with intravenous 
      ZOL 5 mg. Five women experienced APR (APR+) associated with significant decreases 
      in blood lymphocytes and increases in granulocytes and serum CRP. Serum sCTLA-4 
      values were increased in all patients before ZOL administration and decreased 
      significantly 72 h after the ZOL infusion (from 30.0 +/- 2.9 to 6.3 +/- 1.8 ng/ml; 
      p < 0.001) with no differences between APR+ and APR- patients. Consistent with 
      the results of the in vivo study, ZOL (1 muM) decreased the production of sCTLA-4 
      by 87% and 57% after 3 and 5 days in cultures of peripheral blood mononuclear 
      cells (PBMCs) in vitro, respectively, and inhibited the expression of both 
      cytoplasmic and membrane-bound CTLA-4. Our results reveal a novel 
      immunoregulatory action of ZOL that is not related to its action on bone 
      resorption but might be associated with reported clinically significant 
      extraskeletal outcomes of ZOL treatment.
CI  - Copyright (c) 2020 Elsevier Inc. All rights reserved.
FAU - Giusti, Andrea
AU  - Giusti A
AD  - Rheumatology Unit, Department of Musculoskeletal System, Local Health Trust 3, 
      Via Missolungi 14, 16147 Genoa, Italy. Electronic address: 
      andreagiusti6613@gmail.com.
FAU - Camellino, Dario
AU  - Camellino D
AD  - Rheumatology Unit, Department of Musculoskeletal System, Local Health Trust 3, 
      Via Missolungi 14, 16147 Genoa, Italy.
FAU - Saverino, Daniele
AU  - Saverino D
AD  - Laboratory of Autoimmunology, Department of Experimental Medicine, University of 
      Genoa, Via De Toni 14, 16132 Genoa, Italy.
FAU - Iervasi, Erika
AU  - Iervasi E
AD  - Laboratory of Autoimmunology, Department of Experimental Medicine, University of 
      Genoa, Via De Toni 14, 16132 Genoa, Italy.
FAU - Girasole, Giuseppe
AU  - Girasole G
AD  - Rheumatology Unit, Department of Musculoskeletal System, Local Health Trust 3, 
      Via Missolungi 14, 16147 Genoa, Italy.
FAU - Bianchi, Gerolamo
AU  - Bianchi G
AD  - Rheumatology Unit, Department of Musculoskeletal System, Local Health Trust 3, 
      Via Missolungi 14, 16147 Genoa, Italy.
FAU - Papapoulos, Socrates E
AU  - Papapoulos SE
AD  - Rheumatology Unit, Department of Musculoskeletal System, Local Health Trust 3, 
      Via Missolungi 14, 16147 Genoa, Italy; Center for Bone Quality, Leiden University 
      Medical Center, Albinusdreef 2, 2333 ZA Leiden, the Netherlands.
LA  - eng
PT  - Journal Article
DEP - 20200627
PL  - United States
TA  - Bone
JT  - Bone
JID - 8504048
RN  - 0 (CTLA-4 Antigen)
RN  - 0 (Diphosphonates)
RN  - 0 (Imidazoles)
RN  - 6XC1PAD3KF (Zoledronic Acid)
SB  - IM
MH  - *Bone Resorption/drug therapy
MH  - CTLA-4 Antigen
MH  - Diphosphonates/pharmacology/therapeutic use
MH  - Female
MH  - Humans
MH  - Imidazoles/pharmacology/therapeutic use
MH  - *Leukocytes, Mononuclear
MH  - Zoledronic Acid
OTO - NOTNLM
OT  - Acute phase response
OT  - Bisphosphonates
OT  - CTLA-4
OT  - Inflammatory rheumatic diseases
OT  - Zoledronate
COIS- Declaration of competing interest Dr. A. Giusti reports personal fees from UCB, 
      Amgen, Kyowa Kirin, Abiogen Pharma, and Eli Lilly, outside the submitted work. 
      Dr. D. Camellino reports personal fees from AbbVie, Celgene, Janssen-Cilag, Eli 
      Lilly, Medac, Mylan, Novartis, and Sanofi, outside the submitted work. Dr. G. 
      Bianchi reports personal fees from Abbvie, Abiogen Pharma, Amgen, BMS, Celgene, 
      Eli Lilly, GSK, Janssen-Cilag, Medac, MSD, Novartis, Pfizer, Roche, Sanofi, 
      Genzyme, and Servier, outside the submitted work. Prof. S.E. Papapoulos reports 
      personal fees from Amgen, Axsome, Gador, Radius Health, and UCB, outside the 
      submitted work. Prof. D. Saverino, Dr. E. Iervasi and Dr. G. Girasole have 
      nothing to disclose
EDAT- 2020/07/01 06:00
MHDA- 2021/06/22 06:00
CRDT- 2020/07/01 06:00
PHST- 2020/02/20 00:00 [received]
PHST- 2020/06/19 00:00 [revised]
PHST- 2020/06/21 00:00 [accepted]
PHST- 2020/07/01 06:00 [pubmed]
PHST- 2021/06/22 06:00 [medline]
PHST- 2020/07/01 06:00 [entrez]
AID - S8756-3282(20)30292-1 [pii]
AID - 10.1016/j.bone.2020.115512 [doi]
PST - ppublish
SO  - Bone. 2020 Sep;138:115512. doi: 10.1016/j.bone.2020.115512. Epub 2020 Jun 27.