Bone Marrow Contribution to Synovial Hyperplasia Following Joint Surface Injury

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Abstract

Background
Joint surface injury, a known risk factor for osteoarthritis, triggers synovial hyperplasia, which involves proliferation of mesenchymal stromal/stem cells (MSCs). Whether these proliferative MSCs are resident synovial cells or move into the tissue from elsewhere is not known. The aim of this study was to determine the contribution of bone marrow-derived cells to synovial hyperplasia following joint surface injury.

Methods
Lethally irradiated mice were transplanted with green fluorescent protein (GFP)-labelled bone marrow, and MSC chimerism was determined by the colony-forming unit fibroblast (CFU-F) assay and phenotypic analysis. To label host slow-cycling cells prior to bone marrow transplant, mice received iododeoxyuridine for 3 weeks. Mice then were subjected to GFP+ bone marrow transplant, underwent joint surface injury and received chlorodeoxyuridine (CldU) for 7 days to label cells proliferating after injury. GFP- and nucleoside-labelled cells in normal and injured knee joint synovium were quantified in situ by immunofluorescence staining of paraffin-embedded tissue sections. The phenotype of GFP-labelled cells was determined by co-staining for the haematopoietic marker CD16/CD32 and the MSC/fibroblast marker platelet-derived growth factor receptor α (Pdgfrα).

Results
CFU-F assay and phenotypic analysis demonstrated successful bone marrow mesenchymal lineage chimerism in mice that underwent transplants. Bone marrow reconstitution preceded the detection of GFP-labelled cells in synovium. The percentage of GFP+ cells in synovium increased significantly in response to injury, while the proportion of GFP+ cells that were labelled with the proliferation marker CldU did not increase, suggesting that the expansion of the GFP+ cell population in synovium was due mainly to bone marrow cell infiltration. In contrast, proliferation of host slow-cycling cells was significantly increased in the hyperplastic synovium. In both control and injured knee joints, the majority of marrow-derived GFP+ cells in the synovium were haematopoietic (CD16/32+), while a minority of cells expressed the pan-fibroblast/MSC marker Pdgfrα.

Conclusions
Our findings indicate that synovial hyperplasia following joint surface injury involves proliferation of resident slow-cycling cells, with a contribution from infiltrating bone marrow-derived cells. Understanding the process of synovial hyperplasia may reveal ways to restore homeostasis in injured joints and prevent secondary osteoarthritis.
Original languageEnglish
Article number166
Pages (from-to)1-11
Number of pages11
JournalArthritis Research & Therapy
Volume18
DOIs
Publication statusPublished - 13 Jul 2016

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Hyperplasia
Mesenchymal Stromal Cells
Joints
Bone Marrow
Green Fluorescent Proteins
Wounds and Injuries
Synovial Membrane
Bone Marrow Cells
Platelet-Derived Growth Factor Receptors
Chimerism
Fibroblasts
Knee Joint
Transplants
Osteoarthritis
Colony-Forming Units Assay
Staining and Labeling
Idoxuridine
Nucleosides
Paraffin
Fluorescent Antibody Technique

Keywords

  • mesenchymal stem cells
  • stromal cells
  • synovium
  • bone marrow transplantation
  • joint injury

Cite this

@article{aa0de940cfff4a79a30357c78d6b5255,
title = "Bone Marrow Contribution to Synovial Hyperplasia Following Joint Surface Injury",
abstract = "BackgroundJoint surface injury, a known risk factor for osteoarthritis, triggers synovial hyperplasia, which involves proliferation of mesenchymal stromal/stem cells (MSCs). Whether these proliferative MSCs are resident synovial cells or move into the tissue from elsewhere is not known. The aim of this study was to determine the contribution of bone marrow-derived cells to synovial hyperplasia following joint surface injury.MethodsLethally irradiated mice were transplanted with green fluorescent protein (GFP)-labelled bone marrow, and MSC chimerism was determined by the colony-forming unit fibroblast (CFU-F) assay and phenotypic analysis. To label host slow-cycling cells prior to bone marrow transplant, mice received iododeoxyuridine for 3 weeks. Mice then were subjected to GFP+ bone marrow transplant, underwent joint surface injury and received chlorodeoxyuridine (CldU) for 7 days to label cells proliferating after injury. GFP- and nucleoside-labelled cells in normal and injured knee joint synovium were quantified in situ by immunofluorescence staining of paraffin-embedded tissue sections. The phenotype of GFP-labelled cells was determined by co-staining for the haematopoietic marker CD16/CD32 and the MSC/fibroblast marker platelet-derived growth factor receptor α (Pdgfrα).ResultsCFU-F assay and phenotypic analysis demonstrated successful bone marrow mesenchymal lineage chimerism in mice that underwent transplants. Bone marrow reconstitution preceded the detection of GFP-labelled cells in synovium. The percentage of GFP+ cells in synovium increased significantly in response to injury, while the proportion of GFP+ cells that were labelled with the proliferation marker CldU did not increase, suggesting that the expansion of the GFP+ cell population in synovium was due mainly to bone marrow cell infiltration. In contrast, proliferation of host slow-cycling cells was significantly increased in the hyperplastic synovium. In both control and injured knee joints, the majority of marrow-derived GFP+ cells in the synovium were haematopoietic (CD16/32+), while a minority of cells expressed the pan-fibroblast/MSC marker Pdgfrα.ConclusionsOur findings indicate that synovial hyperplasia following joint surface injury involves proliferation of resident slow-cycling cells, with a contribution from infiltrating bone marrow-derived cells. Understanding the process of synovial hyperplasia may reveal ways to restore homeostasis in injured joints and prevent secondary osteoarthritis.",
keywords = "mesenchymal stem cells, stromal cells, synovium, bone marrow transplantation, joint injury",
author = "Ana Sergijenko and Roelofs, {Anke J.} and Riemen, {Anna Helene Katrin} and {De Bari}, Cosimo",
note = "Acknowledgements We thank Dr. Andrea Augello and Dr. Donna MacCallum for advice and help with animal procedures, Susan Clark and Denise Tosh for general technical help and support, and the Arthritis and Regenerative Medicine Laboratory and Arthritis and Musculoskeletal Medicine Programme for general support and scientific discussions. We acknowledge the Iain Fraser Cytometry Centre, the animal facility staff and the Microscopy and Histology Facility, in particular Kevin Mackenzie, Gillian Milne and Lucy Wight for their support. This work was supported by Arthritis Research UK (grants 19271, 19429 and 20050). AHKR is supported by the Wellcome Trust through the Scottish Translational Medicine and Therapeutics Initiative (grant WT 085664).",
year = "2016",
month = "7",
day = "13",
doi = "10.1186/s13075-016-1060-8",
language = "English",
volume = "18",
pages = "1--11",
journal = "Arthritis Research & Therapy",
issn = "1478-6354",
publisher = "BioMed Central",

}

TY - JOUR

T1 - Bone Marrow Contribution to Synovial Hyperplasia Following Joint Surface Injury

AU - Sergijenko, Ana

AU - Roelofs, Anke J.

AU - Riemen, Anna Helene Katrin

AU - De Bari, Cosimo

N1 - Acknowledgements We thank Dr. Andrea Augello and Dr. Donna MacCallum for advice and help with animal procedures, Susan Clark and Denise Tosh for general technical help and support, and the Arthritis and Regenerative Medicine Laboratory and Arthritis and Musculoskeletal Medicine Programme for general support and scientific discussions. We acknowledge the Iain Fraser Cytometry Centre, the animal facility staff and the Microscopy and Histology Facility, in particular Kevin Mackenzie, Gillian Milne and Lucy Wight for their support. This work was supported by Arthritis Research UK (grants 19271, 19429 and 20050). AHKR is supported by the Wellcome Trust through the Scottish Translational Medicine and Therapeutics Initiative (grant WT 085664).

PY - 2016/7/13

Y1 - 2016/7/13

N2 - BackgroundJoint surface injury, a known risk factor for osteoarthritis, triggers synovial hyperplasia, which involves proliferation of mesenchymal stromal/stem cells (MSCs). Whether these proliferative MSCs are resident synovial cells or move into the tissue from elsewhere is not known. The aim of this study was to determine the contribution of bone marrow-derived cells to synovial hyperplasia following joint surface injury.MethodsLethally irradiated mice were transplanted with green fluorescent protein (GFP)-labelled bone marrow, and MSC chimerism was determined by the colony-forming unit fibroblast (CFU-F) assay and phenotypic analysis. To label host slow-cycling cells prior to bone marrow transplant, mice received iododeoxyuridine for 3 weeks. Mice then were subjected to GFP+ bone marrow transplant, underwent joint surface injury and received chlorodeoxyuridine (CldU) for 7 days to label cells proliferating after injury. GFP- and nucleoside-labelled cells in normal and injured knee joint synovium were quantified in situ by immunofluorescence staining of paraffin-embedded tissue sections. The phenotype of GFP-labelled cells was determined by co-staining for the haematopoietic marker CD16/CD32 and the MSC/fibroblast marker platelet-derived growth factor receptor α (Pdgfrα).ResultsCFU-F assay and phenotypic analysis demonstrated successful bone marrow mesenchymal lineage chimerism in mice that underwent transplants. Bone marrow reconstitution preceded the detection of GFP-labelled cells in synovium. The percentage of GFP+ cells in synovium increased significantly in response to injury, while the proportion of GFP+ cells that were labelled with the proliferation marker CldU did not increase, suggesting that the expansion of the GFP+ cell population in synovium was due mainly to bone marrow cell infiltration. In contrast, proliferation of host slow-cycling cells was significantly increased in the hyperplastic synovium. In both control and injured knee joints, the majority of marrow-derived GFP+ cells in the synovium were haematopoietic (CD16/32+), while a minority of cells expressed the pan-fibroblast/MSC marker Pdgfrα.ConclusionsOur findings indicate that synovial hyperplasia following joint surface injury involves proliferation of resident slow-cycling cells, with a contribution from infiltrating bone marrow-derived cells. Understanding the process of synovial hyperplasia may reveal ways to restore homeostasis in injured joints and prevent secondary osteoarthritis.

AB - BackgroundJoint surface injury, a known risk factor for osteoarthritis, triggers synovial hyperplasia, which involves proliferation of mesenchymal stromal/stem cells (MSCs). Whether these proliferative MSCs are resident synovial cells or move into the tissue from elsewhere is not known. The aim of this study was to determine the contribution of bone marrow-derived cells to synovial hyperplasia following joint surface injury.MethodsLethally irradiated mice were transplanted with green fluorescent protein (GFP)-labelled bone marrow, and MSC chimerism was determined by the colony-forming unit fibroblast (CFU-F) assay and phenotypic analysis. To label host slow-cycling cells prior to bone marrow transplant, mice received iododeoxyuridine for 3 weeks. Mice then were subjected to GFP+ bone marrow transplant, underwent joint surface injury and received chlorodeoxyuridine (CldU) for 7 days to label cells proliferating after injury. GFP- and nucleoside-labelled cells in normal and injured knee joint synovium were quantified in situ by immunofluorescence staining of paraffin-embedded tissue sections. The phenotype of GFP-labelled cells was determined by co-staining for the haematopoietic marker CD16/CD32 and the MSC/fibroblast marker platelet-derived growth factor receptor α (Pdgfrα).ResultsCFU-F assay and phenotypic analysis demonstrated successful bone marrow mesenchymal lineage chimerism in mice that underwent transplants. Bone marrow reconstitution preceded the detection of GFP-labelled cells in synovium. The percentage of GFP+ cells in synovium increased significantly in response to injury, while the proportion of GFP+ cells that were labelled with the proliferation marker CldU did not increase, suggesting that the expansion of the GFP+ cell population in synovium was due mainly to bone marrow cell infiltration. In contrast, proliferation of host slow-cycling cells was significantly increased in the hyperplastic synovium. In both control and injured knee joints, the majority of marrow-derived GFP+ cells in the synovium were haematopoietic (CD16/32+), while a minority of cells expressed the pan-fibroblast/MSC marker Pdgfrα.ConclusionsOur findings indicate that synovial hyperplasia following joint surface injury involves proliferation of resident slow-cycling cells, with a contribution from infiltrating bone marrow-derived cells. Understanding the process of synovial hyperplasia may reveal ways to restore homeostasis in injured joints and prevent secondary osteoarthritis.

KW - mesenchymal stem cells

KW - stromal cells

KW - synovium

KW - bone marrow transplantation

KW - joint injury

U2 - 10.1186/s13075-016-1060-8

DO - 10.1186/s13075-016-1060-8

M3 - Article

VL - 18

SP - 1

EP - 11

JO - Arthritis Research & Therapy

JF - Arthritis Research & Therapy

SN - 1478-6354

M1 - 166

ER -