PMID- 35688363
OWN - NLM
STAT- MEDLINE
DCOM- 20220720
LR  - 20220803
IS  - 1873-2763 (Electronic)
IS  - 1873-2763 (Linking)
VI  - 162
DP  - 2022 Sep
TI  - Pharmacological inhibition of DKK1 promotes spine fusion in an ovariectomized rat 
      model.
PG  - 116456
LID - S8756-3282(22)00133-8 [pii]
LID - 10.1016/j.bone.2022.116456 [doi]
AB  - Osteoporosis is common in patients undergoing spine surgery, and carries a 
      considerable risk of adverse outcomes. New methods to positively influence bone 
      regeneration and spine fusion under osteoporotic conditions would be impactful. 
      Neutralizing anti-Dickkopf-1 (DKK1) antibodies has been used as a bone anabolic 
      agent, and recently reported by our group to aid in stem cell-mediated 
      appendicular bone regeneration. Here, a small molecule designed as a DKK1 
      inhibitor, WAY-262611, was used to induce posterolateral spine fusion in an 
      ovariectomized rat model. In vitro, pharmacological inhibition of DKK1 enhanced 
      osteogenesis and Wnt signaling activity among rat bone marrow-derived 
      stem/stromal cells (BMSCs). In vivo, systemic treatment with WAY-262611 promoted 
      both chondrogenesis and osteogenesis within the spinal fusion site, and 
      ultimately led to significant improvements in lumbar fusion as assessed by XR, 
      muCT, histology and manual palpation assessments. No significant effect on 
      osteoclast numbers or fusion site angiogenesis was detected, suggesting a primary 
      direct effect on mesenchymal cells of the implantation site. Finally, evidence 
      from human stem/stromal cells further demonstrated that pharmacologic inhibition 
      of DKK1 promoted osteogenic differentiation in vitro. Taken together, our results 
      suggest that targeting DKK1 promotes local bone formation and suggests potential 
      clinical value for osteoporotic bone repair.
CI  - Copyright (c) 2022 Elsevier Inc. All rights reserved.
FAU - Li, Zhao
AU  - Li Z
AD  - Department of Pathology, Johns Hopkins University, Baltimore, MD 21205,USA.
FAU - Xing, Xin
AU  - Xing X
AD  - Department of Pathology, Johns Hopkins University, Baltimore, MD 21205,USA.
FAU - Gomez-Salazar, Mario Armando
AU  - Gomez-Salazar MA
AD  - Department of Pathology, Johns Hopkins University, Baltimore, MD 21205,USA.
FAU - Xu, Mingxin
AU  - Xu M
AD  - Department of Pathology, Johns Hopkins University, Baltimore, MD 21205,USA.
FAU - Negri, Stefano
AU  - Negri S
AD  - Department of Pathology, Johns Hopkins University, Baltimore, MD 21205,USA; 
      Department of Orthopaedics and Traumatology, University of Verona, Verona 37129, 
      Italy.
FAU - Xu, Jiajia
AU  - Xu J
AD  - Department of Pathology, Johns Hopkins University, Baltimore, MD 21205,USA.
FAU - James, Aaron W
AU  - James AW
AD  - Department of Pathology, Johns Hopkins University, Baltimore, MD 21205,USA. 
      Electronic address: awjames@jhmi.edu.
LA  - eng
GR  - R21 DE027922/DE/NIDCR NIH HHS/United States
GR  - R01 DE031028/DE/NIDCR NIH HHS/United States
GR  - R01 AR070773/AR/NIAMS NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20220608
PL  - United States
TA  - Bone
JT  - Bone
JID - 8504048
RN  - 0 (Dkk1 protein, rat)
RN  - 0 (Intercellular Signaling Peptides and Proteins)
RN  - 0 (Naphthalenes)
RN  - 0 (Piperidines)
RN  - 0 (Pyrimidines)
RN  - 0 (WAY-262611)
SB  - IM
MH  - Animals
MH  - Cell Differentiation
MH  - Female
MH  - Humans
MH  - Intercellular Signaling Peptides and Proteins
MH  - *Mesenchymal Stem Cells
MH  - *Naphthalenes/pharmacology
MH  - Osteogenesis
MH  - *Osteoporosis/drug therapy
MH  - Ovariectomy
MH  - *Piperidines/pharmacology
MH  - *Pyrimidines/pharmacology
MH  - Rats
MH  - Wnt Signaling Pathway
OTO - NOTNLM
OT  - Bone repair
OT  - DKK1
OT  - Osteoporosis
OT  - Small-molecule inhibitors
OT  - Spine fusion
OT  - Wnt signaling
EDAT- 2022/06/11 06:00
MHDA- 2022/07/22 06:00
CRDT- 2022/06/10 19:26
PHST- 2022/03/23 00:00 [received]
PHST- 2022/05/31 00:00 [revised]
PHST- 2022/06/01 00:00 [accepted]
PHST- 2022/06/11 06:00 [pubmed]
PHST- 2022/07/22 06:00 [medline]
PHST- 2022/06/10 19:26 [entrez]
AID - S8756-3282(22)00133-8 [pii]
AID - 10.1016/j.bone.2022.116456 [doi]
PST - ppublish
SO  - Bone. 2022 Sep;162:116456. doi: 10.1016/j.bone.2022.116456. Epub 2022 Jun 8.