PMID- 38040717
OWN - NLM
STAT- PubMed-not-MEDLINE
LR  - 20231205
IS  - 2058-7716 (Print)
IS  - 2058-7716 (Electronic)
IS  - 2058-7716 (Linking)
VI  - 9
IP  - 1
DP  - 2023 Dec 1
TI  - Metallothionein 3 promotes osteoclast differentiation and survival by regulating 
      the intracellular Zn(2+) concentration and NRF2 pathway.
PG  - 436
LID - 10.1038/s41420-023-01729-y [doi]
LID - 436
AB  - In osteoclastogenesis, the metabolism of metal ions plays an essential role in 
      controlling reactive oxygen species (ROS) production, mitochondrial biogenesis, 
      and survival, and differentiation. However, the mechanism regulating metal ions 
      during osteoclast differentiation remains unclear. The metal-binding protein 
      metallothionein (MT) detoxifies heavy metals, maintains metal ion homeostasis, 
      especially zinc, and manages cellular redox levels. We carried out tests using 
      murine osteoclast precursors to examine the function of MT in osteoclastogenesis 
      and evaluated their potential as targets for future osteoporosis treatments. MT 
      genes were significantly upregulated upon differentiation from osteoclast 
      precursors to mature osteoclasts in response to receptor activators of nuclear 
      factor-kappaB (NF-kappaB) ligand (RANKL) stimulation, and MT3 expression was particularly 
      pronounced in mature osteoclasts among MT genes. The knockdown of MT3 in 
      osteoclast precursors demonstrated a remarkable inhibition of differentiation 
      into mature osteoclasts. In preosteoclasts, MT3 knockdown suppressed the activity 
      of mitogen-activated protein kinase (MAPK) and NF-kappaB signaling pathways upon 
      RANKL stimulation, leading to affect cell survival through elevated cleaved 
      Caspase 3 and poly (ADP-ribose) polymerase (PARP) levels. Additionally, ROS 
      levels were decreased, and nuclear factor erythroid 2-related factor 2 (NRF2) (a 
      suppressor of ROS) and the downstream antioxidant proteins, such as catalase 
      (CAT) and heme oxygenase 1 (HO-1), were more highly expressed in the MT3 
      preosteoclast knockdowns. mitochondrial ROS, which is involved in mitochondrial 
      biogenesis and the production of reactive oxygen species, were similarly 
      decreased because cAMP response element-binding (CREB) and peroxisome 
      proliferator-activated receptor gamma coactivator 1beta (PGC-1beta) were less activated due 
      to MT3 depletion. Thus, by modulating ROS through the NRF2 pathway, MT3 plays a 
      crucial role in regulating osteoclast differentiation and survival, acting as a 
      metabolic modulator of intracellular zinc ions.
CI  - (c) 2023. The Author(s).
FAU - Arisumi, Shinkichi
AU  - Arisumi S
AD  - Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu 
      University, Fukuoka, Japan.
FAU - Fujiwara, Toshifumi
AU  - Fujiwara T
AUID- ORCID: 0000-0001-9381-9696
AD  - Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu 
      University, Fukuoka, Japan. fujiwara.toshifumi.771@m.kyushu-u.ac.jp.
FAU - Yasumoto, Keitaro
AU  - Yasumoto K
AD  - Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu 
      University, Fukuoka, Japan.
FAU - Tsutsui, Tomoko
AU  - Tsutsui T
AD  - Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu 
      University, Fukuoka, Japan.
FAU - Saiwai, Hirokazu
AU  - Saiwai H
AD  - Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu 
      University, Fukuoka, Japan.
FAU - Kobayakawa, Kazu
AU  - Kobayakawa K
AD  - Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu 
      University, Fukuoka, Japan.
FAU - Okada, Seiji
AU  - Okada S
AD  - Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Osaka 
      University, Suita, Japan.
FAU - Zhao, Haibo
AU  - Zhao H
AD  - Southern California Institute for Research and Education, Long Beach, CA, USA.
AD  - Center for Osteoporosis and Metabolic Bone Diseases, Division of Endocrinology, 
      Department of Internal Medicine, University of Arkansas for Medical Sciences, 
      Little Rock, USA.
AD  - Department of Physiology and Cell Biology, University of Arkansas for Medical 
      Sciences, Little Rock, USA.
FAU - Nakashima, Yasuharu
AU  - Nakashima Y
AD  - Department of Orthopaedic Surgery, Graduate School of Medical Sciences, Kyushu 
      University, Fukuoka, Japan.
LA  - eng
GR  - JP18K16626/MEXT | Japan Society for the Promotion of Science (JSPS)/
GR  - 22K09359/MEXT | Japan Society for the Promotion of Science (JSPS)/
PT  - Journal Article
DEP - 20231201
PL  - United States
TA  - Cell Death Discov
JT  - Cell death discovery
JID - 101665035
PMC - PMC10692135
COIS- The authors declare no competing interests.
EDAT- 2023/12/02 00:41
MHDA- 2023/12/02 00:42
PMCR- 2023/12/01
CRDT- 2023/12/01 23:18
PHST- 2023/09/22 00:00 [received]
PHST- 2023/11/16 00:00 [accepted]
PHST- 2023/11/06 00:00 [revised]
PHST- 2023/12/02 00:42 [medline]
PHST- 2023/12/02 00:41 [pubmed]
PHST- 2023/12/01 23:18 [entrez]
PHST- 2023/12/01 00:00 [pmc-release]
AID - 10.1038/s41420-023-01729-y [pii]
AID - 1729 [pii]
AID - 10.1038/s41420-023-01729-y [doi]
PST - epublish
SO  - Cell Death Discov. 2023 Dec 1;9(1):436. doi: 10.1038/s41420-023-01729-y.