title: The Oncogene LRF Stimulates Proliferation of Mesenchymal Stem Cells and Inhibits Their Chondrogenic Differentiation.
abstract: OBJECTIVE
  The oncogene leukemia/lymphoma-related factor (LRF) enhances chondrosarcoma proliferation and malignancy. This study aimed to investigate the roles of LRF in chondrogenic differentiation of primary human bone marrow-derived mesenchymal stem cells (BMSCs).
  
  
  METHODS
  LRF was overexpressed in BMSC by lentiviral transduction. Chondrogenic differentiation of BMSC was induced by high-density pellet culture. Western blotting and real-time polymerase chain reaction were used to investigate changes in protein and mRNA levels, respectively, during chondrogenesis. Safranin-O staining, immunohistochemistry, and glycoaminoglycan contents were used to assess cartilage matrix deposition. BMSC proliferation was determined by mitochondrial dehydrogenase activity and cell counting. Cell cycle profiling was performed by flow cytometry.
  
  
  RESULTS
  LRF overexpression effectively inhibited protein and mRNA expression of chondrocyte markers and cartilage matrix deposition during chondrogenesis of BMSC. Endogenous LRF expression was constitutively high in undifferentiated BMSC but remained low in primary articular chondrocytes. Endogenous LRF protein was downregulated in a time-dependent manner during chondrogenesis. BMSCs overexpressing LRF had higher proliferation rates and cell population in the S phase. LRF suppressed p53 expression during chondrogenesis and this might prevent differentiating chondrocytes from entering a quiescent state.
  
  
  CONCLUSIONS
  Our data showed that LRF is important for stimulating stem cell proliferation and cell cycle progression. It is known that LRF is highly expressed in the mouse limb buds prior to overt chondrogenesis; thus, LRF might function to prevent premature chondrogenic differentiation of stem cells.
authors.affiliation: Department of Orthopaedic Surgery, Lawrence J. Ellison Musculoskeletal Research Center, University of California Davis Medical Center, Sacramento, CA, USA.
authors.forename: Jasper H N
authors.initials: JH
authors.lastname: Yik
authors.affiliation: Department of Orthopaedic Surgery, Lawrence J. Ellison Musculoskeletal Research Center, University of California Davis Medical Center, Sacramento, CA, USA.
authors.forename: Huan
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Orthopaedic Surgery, Lawrence J. Ellison Musculoskeletal Research Center, University of California Davis Medical Center, Sacramento, CA, USA.
authors.forename: Chitrangada
authors.initials: C
authors.lastname: Acharya
authors.affiliation: Department of Orthopaedic Surgery, Lawrence J. Ellison Musculoskeletal Research Center, University of California Davis Medical Center, Sacramento, CA, USA.
authors.forename: Ratna
authors.initials: R
authors.lastname: Kumari
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, Stem Cell Program, University of California Davis Medical Center, Sacramento, CA, USA.
authors.forename: Fernando
authors.initials: F
authors.lastname: Fierro
authors.affiliation: Department of Orthopaedic Surgery, Lawrence J. Ellison Musculoskeletal Research Center, University of California Davis Medical Center, Sacramento, CA, USA.
authors.forename: Dominik R
authors.initials: DR
authors.lastname: Haudenschild
authors.affiliation: Department of Internal Medicine, Division of Hematology/Oncology, Stem Cell Program, University of California Davis Medical Center, Sacramento, CA, USA.
authors.forename: Jan
authors.initials: J
authors.lastname: Nolta
authors.affiliation: Department of Orthopaedic Surgery, Lawrence J. Ellison Musculoskeletal Research Center, University of California Davis Medical Center, Sacramento, CA, USA.
authors.forename: Paul E
authors.initials: PE
authors.lastname: Di Cesare
keywords: LRF; cells; chondrocytes; chondrogenesis; mesenchymal stem cells; proliferation