PMID- 32545756
OWN - NLM
STAT- MEDLINE
DCOM- 20210219
LR  - 20210219
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 21
IP  - 12
DP  - 2020 Jun 13
TI  - Augmentation of Bone Regeneration by Depletion of Stress-Induced Senescent Cells 
      Using Catechin and Senolytics.
LID - 10.3390/ijms21124213 [doi]
LID - 4213
AB  - Despite advances in bone regenerative medicine, the relationship between 
      stress-induced premature senescence (SIPS) in cells and bone regeneration remains 
      largely unknown. Herein, we demonstrated that the implantation of a 
      lipopolysaccharide (LPS) sustained-release gelatin sponge (LS-G) increases the 
      number of SIPS cells and that the elimination of these cells promotes bone 
      formation in critical-sized bone defects in the rat calvaria. Histological 
      (hematoxylin-eosin and SA-beta-gal) and immunohistological (p16 and p21 for 
      analyzing cellular senescence and 4-HNE for oxidation) staining was used to 
      identify SIPS cells and elucidate the underlying mechanism. Bone formation in 
      defects were analyzed using microcomputed tomography, one and four weeks after 
      surgery. Parallel to LS-G implantation, local epigallocatechin gallate (EGCG) 
      administration, and systemic senolytic (dasatinib and quercetin: D+Q) 
      administration were used to eliminate SIPS cells. After LS-G implantation, 
      SA-beta-gal-, p16-, and p21-positive cells (SIPS cells) accumulated in the defects. 
      However, treatment with LS-G+EGCG and LS-G+D+Q resulted in lower numbers of SIPS 
      cells than that with LS-G in the defects, resulting in an augmentation of newly 
      formed bone. We demonstrated that SIPS cells induced by sustained stimulation by 
      LPS may play a deleterious role in bone formation. Controlling these cell numbers 
      is a promising strategy to increase bone regeneration.
FAU - Honda, Yoshitomo
AU  - Honda Y
AUID- ORCID: 0000-0002-4392-2318
AD  - Institute of Dental Research, Osaka Dental University, 8-1, Kuzuhahanazonocho, 
      Hirakata, Osaka 573-1121, Japan.
FAU - Huang, Anqi
AU  - Huang A
AD  - Department of Oral Implantology, Osaka Dental University, 1-5-17, Otemae, 
      Chuo-ku, Osaka 540-0008, Japan.
FAU - Tanaka, Tomonari
AU  - Tanaka T
AUID- ORCID: 0000-0002-7050-9043
AD  - Graduate School of Science and Technology, Kyoto Institute of Technology, 
      Matsugasaki, Sakyo-ku, Kyoto 606-8585, Japan.
FAU - Han, Xiaoyu
AU  - Han X
AD  - Department of Operative Dentistry, Osaka Dental University, 1-5-17, Otemae, 
      Chuo-ku, Osaka 540-0008, Japan.
FAU - Gao, Beiyuan
AU  - Gao B
AD  - Department of Oral Implantology, Osaka Dental University, 1-5-17, Otemae, 
      Chuo-ku, Osaka 540-0008, Japan.
FAU - Liu, Haitao
AU  - Liu H
AD  - Department of Operative Dentistry, Osaka Dental University, 1-5-17, Otemae, 
      Chuo-ku, Osaka 540-0008, Japan.
FAU - Wang, Xinchen
AU  - Wang X
AD  - Department of Orthodontics, Osaka Dental University, 1-5-17, Otemae, Chuo-ku, 
      Osaka 540-0008, Japan.
FAU - Zhao, Jianxin
AU  - Zhao J
AD  - Department of Orthodontics, Osaka Dental University, 1-5-17, Otemae, Chuo-ku, 
      Osaka 540-0008, Japan.
FAU - Hashimoto, Yoshiya
AU  - Hashimoto Y
AUID- ORCID: 0000-0002-7082-5804
AD  - Department of Biomaterials, Osaka Dental University, 8-1, Kuzuhahanazonocho, 
      Hirakata, Osaka 573-1121, Japan.
FAU - Yamamoto, Kazuyo
AU  - Yamamoto K
AD  - Department of Operative Dentistry, Osaka Dental University, 1-5-17, Otemae, 
      Chuo-ku, Osaka 540-0008, Japan.
FAU - Matsumoto, Naoyuki
AU  - Matsumoto N
AD  - Department of Orthodontics, Osaka Dental University, 1-5-17, Otemae, Chuo-ku, 
      Osaka 540-0008, Japan.
FAU - Baba, Shunsuke
AU  - Baba S
AD  - Department of Oral Implantology, Osaka Dental University, 1-5-17, Otemae, 
      Chuo-ku, Osaka 540-0008, Japan.
FAU - Umeda, Makoto
AU  - Umeda M
AD  - Institute of Dental Research, Osaka Dental University, 8-1, Kuzuhahanazonocho, 
      Hirakata, Osaka 573-1121, Japan.
AD  - Department of Periodontology, Osaka Dental University, 1-5-17, Otemae, Chuo-ku, 
      Osaka 540-0008, Japan.
LA  - eng
GR  - 16K11667 and 18H02986/Japan Society for the Promotion of Science/
PT  - Journal Article
DEP - 20200613
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Aldehydes)
RN  - 0 (Bone Substitutes)
RN  - 0 (Delayed-Action Preparations)
RN  - 0 (Lipopolysaccharides)
RN  - 8R1V1STN48 (Catechin)
RN  - 9IKM0I5T1E (Quercetin)
RN  - BQM438CTEL (epigallocatechin gallate)
RN  - K1CVM13F96 (4-hydroxy-2-nonenal)
RN  - RBZ1571X5H (Dasatinib)
SB  - IM
MH  - Aldehydes/metabolism
MH  - Animals
MH  - Bone Regeneration/drug effects
MH  - Bone Substitutes/*administration & dosage/chemistry/pharmacology
MH  - Catechin/*administration & dosage/*analogs & derivatives/chemistry/pharmacology
MH  - Cell Line
MH  - Cellular Senescence
MH  - Dasatinib/*administration & dosage/pharmacology
MH  - Delayed-Action Preparations
MH  - Lipopolysaccharides/pharmacology
MH  - Osteoblasts/*cytology/drug effects/metabolism
MH  - Quercetin/*administration & dosage/pharmacology
MH  - Rats
MH  - Skull/diagnostic imaging/drug effects/*injuries
MH  - X-Ray Microtomography
PMC - PMC7352429
OTO - NOTNLM
OT  - EGCG
OT  - LPS
OT  - bone formation
OT  - catechin
OT  - cellular senescence
OT  - senolytics
COIS- The authors declare no conflict of interest. The funders had no role in the 
      design of the study; in the collection, analyses, or interpretation of data; in 
      the writing of the manuscript, or in the decision to publish the results.
EDAT- 2020/06/18 06:00
MHDA- 2021/02/20 06:00
PMCR- 2020/06/01
CRDT- 2020/06/18 06:00
PHST- 2020/05/15 00:00 [received]
PHST- 2020/06/07 00:00 [revised]
PHST- 2020/06/11 00:00 [accepted]
PHST- 2020/06/18 06:00 [entrez]
PHST- 2020/06/18 06:00 [pubmed]
PHST- 2021/02/20 06:00 [medline]
PHST- 2020/06/01 00:00 [pmc-release]
AID - ijms21124213 [pii]
AID - ijms-21-04213 [pii]
AID - 10.3390/ijms21124213 [doi]
PST - epublish
SO  - Int J Mol Sci. 2020 Jun 13;21(12):4213. doi: 10.3390/ijms21124213.