PMID- 29710775
OWN - NLM
STAT- MEDLINE
DCOM- 20180911
LR  - 20181114
IS  - 1422-0067 (Electronic)
IS  - 1422-0067 (Linking)
VI  - 19
IP  - 5
DP  - 2018 Apr 28
TI  - Novel Ex Vivo Human Osteochondral Explant Model of Knee and Spine Osteoarthritis 
      Enables Assessment of Inflammatory and Drug Treatment Responses.
LID - 10.3390/ijms19051314 [doi]
LID - 1314
AB  - Osteoarthritis of the knee and spine is highly prevalent in modern society, yet a 
      disease-modifying pharmacological treatment remains an unmet clinical need. A 
      major challenge for drug development includes selection of appropriate 
      preclinical models that accurately reflect clinical phenotypes of human disease. 
      The aim of this study was to establish an ex vivo explant model of human knee and 
      spine osteoarthritis that enables assessment of osteochondral tissue responses to 
      inflammation and drug treatment. Equal-sized osteochondral fragments from knee 
      and facet joints (both n = 6) were subjected to explant culture for 7 days in the 
      presence of a toll-like receptor 4 (TLR4) agonist and an inhibitor of 
      transforming growth factor-beta (TGF-β) receptor type I signaling. Markers 
      of inflammation, interleukin-6 (IL-6) and monocyte chemoattractant protein-1 
      (MCP-1), but not bone metabolism (pro-collagen-I) were significantly increased by 
      treatment with TLR4 agonist. Targeting of TGF-β signaling resulted in a 
      strong reduction of pro-collagen-I and significantly decreased IL-6 levels. MCP-1 
      secretion was increased, revealing a regulatory feedback mechanism between 
      TGF-β and MCP-1 in joint tissues. These findings demonstrate 
      proof-of-concept and feasibility of explant culture of human osteochondral 
      specimens as a preclinical disease model, which might aid in definition and 
      validation of disease-modifying drug targets.
FAU - Geurts, Jeroen
AU  - Geurts J
AUID- ORCID: 0000-0002-4367-4641
AD  - Department of Spine Surgery, University Hospital of Basel, 4031 Basel, 
      Switzerland. Jeroen.Geurts@usb.ch.
AD  - Department of Biomedical Engineering, University Hospital of Basel, 4123 
      Allschwil, Switzerland. Jeroen.Geurts@usb.ch.
FAU - Juric, Doria
AU  - Juric D
AD  - Department of Biomedical Engineering, University Hospital of Basel, 4123 
      Allschwil, Switzerland. doria.j@hotmail.com.
FAU - Muller, Miriam
AU  - Muller M
AD  - Department of Biomedical Engineering, University Hospital of Basel, 4123 
      Allschwil, Switzerland. MiriamMWeil@web.de.
AD  - Institute for Chemistry and Bioanalytics, University of Applied Sciences and Art 
      Northwestern Switzerland, 4132 Muttenz, Switzerland. MiriamMWeil@web.de.
FAU - Scharen, Stefan
AU  - Scharen S
AD  - Department of Spine Surgery, University Hospital of Basel, 4031 Basel, 
      Switzerland. Stefan.Schaeren@usb.ch.
FAU - Netzer, Cordula
AU  - Netzer C
AD  - Department of Spine Surgery, University Hospital of Basel, 4031 Basel, 
      Switzerland. Cordula.Netzer@usb.ch.
LA  - eng
PT  - Journal Article
DEP - 20180428
PL  - Switzerland
TA  - Int J Mol Sci
JT  - International journal of molecular sciences
JID - 101092791
RN  - 0 (Anti-Inflammatory Agents)
RN  - 0 (CCL2 protein, human)
RN  - 0 (Chemokine CCL2)
RN  - 0 (Collagen Type I)
RN  - 0 (Interleukin-1)
RN  - 0 (Receptors, Transforming Growth Factor beta)
RN  - 0 (Toll-Like Receptor 4)
SB  - IM
MH  - Aged
MH  - Anti-Inflammatory Agents/*pharmacology
MH  - Chemokine CCL2/genetics/metabolism
MH  - Collagen Type I/genetics/metabolism
MH  - Drug Evaluation, Preclinical/*methods
MH  - Humans
MH  - Interleukin-1/metabolism
MH  - Joints/drug effects
MH  - Middle Aged
MH  - Osteoarthritis, Knee/metabolism/*pathology
MH  - Osteoarthritis, Spine/metabolism/*pathology
MH  - Receptors, Transforming Growth Factor beta/antagonists & inhibitors
MH  - Spinal Osteochondrosis/metabolism/*pathology
MH  - Tissue Culture Techniques/*methods
MH  - Toll-Like Receptor 4/agonists
PMC - PMC5983625
OTO - NOTNLM
OT  - bone metabolism
OT  - experimental model
OT  - inflammation
OT  - knee
OT  - osteoarthritis
OT  - osteochondral
OT  - spine
COIS- The authors declare no conflict of interest. The funding sponsors had no role in 
      the design of the study; in the collection, analyses, or interpretation of data; 
      in the writing of the manuscript, and in the decision to publish the results.
EDAT- 2018/05/02 06:00
MHDA- 2018/09/12 06:00
PMCR- 2018/05/01
CRDT- 2018/05/02 06:00
PHST- 2018/01/31 00:00 [received]
PHST- 2018/03/20 00:00 [revised]
PHST- 2018/04/17 00:00 [accepted]
PHST- 2018/05/02 06:00 [entrez]
PHST- 2018/05/02 06:00 [pubmed]
PHST- 2018/09/12 06:00 [medline]
PHST- 2018/05/01 00:00 [pmc-release]
AID - ijms19051314 [pii]
AID - ijms-19-01314 [pii]
AID - 10.3390/ijms19051314 [doi]
PST - epublish
SO  - Int J Mol Sci. 2018 Apr 28;19(5):1314. doi: 10.3390/ijms19051314.