title: Hypoxia-inducible factor 3-alpha expression is associated with the stable chondrocyte phenotype.
abstract: The hypoxia-inducible factors HIF-1α and HIF-2α are important regulators of the chondrocyte phenotype but little is known about HIF-3α in cartilage. The objective of this study was to characterize HIF-3α (HIF3A) expression during chondrocyte differentiation in vitro and in native cartilage tissues. HIF3A, COL10A1, and MMP13 were quantified in mesenchymal stem cells (MSCs) and articular chondrocytes from healthy and osteoarthritic (OA) tissue in three-dimensional cultures and in human embryonic epiphyses and adult articular cartilage. HIF3A was found to have an inverse association with hypertrophic markers COL10A1 and MMP13 in chondrogenic cells and tissues. In healthy chondrocytes, HIF3A was induced by dexamethasone and increased during redifferentiation. By comparison, HIF3A expression was extremely low in chondrogenically differentiated MSCs expressing high levels of COL10A1 and MMP13. HIF3A was also lower in redifferentiated OA chondrocytes than in healthy chondrocytes. In human embryonic epiphyseal tissue, HIF3A expression was lowest in the hypertrophic zone. Distinct splice patterns were also found in embryonic cartilage when compared with adult articular cartilage and redifferentiated chondrocytes. These in vitro and in vivo findings suggest that HIF3A levels are indicative of the hypertrophic state of chondrogenic cells and one or more splice variants may be important regulators of the chondrocyte phenotype.
authors.affiliation: Department of Orthopaedics and Rehabilitation, Oregon Health & Science University, Portland, Oregon.
authors.forename: Brandon D
authors.initials: BD
authors.lastname: Markway
authors.affiliation: Department of Orthopaedics and Rehabilitation, Oregon Health & Science University, Portland, Oregon.
authors.forename: Holly
authors.initials: H
authors.lastname: Cho
authors.affiliation: Department of Orthopaedics and Rehabilitation, Oregon Health & Science University, Portland, Oregon.
authors.forename: Jevgenia
authors.initials: J
authors.lastname: Zilberman-Rudenko
authors.affiliation: Department of Orthopaedics and Rehabilitation, Oregon Health & Science University, Portland, Oregon.
authors.forename: Paul
authors.initials: P
authors.lastname: Holden
authors.affiliation: Department of Orthopaedic Surgery, Musculoskeletal Research Center, Washington University, St. Louis, Missouri.
authors.forename: Audrey
authors.initials: A
authors.lastname: McAlinden
authors.affiliation: Department of Orthopaedics and Rehabilitation, Oregon Health & Science University, Portland, Oregon.
authors.forename: Brian
authors.initials: B
authors.lastname: Johnstone
mesh_terms: D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism*; D002358:Cartilage, Articular / Q000196:embryology; D002454:Cell Differentiation; D002478:Cells, Cultured; D019902:Chondrocytes / Q000166:cytology* / Q000378:metabolism; D020219:Chondrogenesis; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D010003:Osteoarthritis / Q000378:metabolism; D010641:Phenotype; D012097:Repressor Proteins
chemical_list: D051017:Apoptosis Regulatory Proteins; D051792:Basic Helix-Loop-Helix Proteins; D012097:Repressor Proteins; C116973:HIF3A protein, human
keywords: cartilage; hypertrophy; hypoxia; mesenchymal stem cells; osteoarthritis