title: Parathyroid hormone-related protein is induced by hypoxia and promotes expression of the differentiated phenotype of human articular chondrocytes.
abstract: PTHrP (parathyroid hormone-related protein) is crucial for normal cartilage development and long bone growth and acts to delay chondrocyte hypertrophy and terminal differentiation in the growth plate. After growth plate closure adult HACs (human articular chondrocytes) still produce PTHrP, suggesting a possible role for this factor in the permanent articular cartilage. However, the expression regulation and function of PTHrP in the permanent articular cartilage is unknown. Human articular cartilage is an avascular tissue and functions in a hypoxic environment. The resident chondrocytes have adapted to hypoxia and use it to drive their tissue-specific functions. In the present study, we explored directly in normal articular chondrocytes isolated from a range of human donors the effect of hypoxia on PTHrP expression and whether PTHrP can regulate the expression of the permanent articular chondrocyte phenotype. We show that in HACs PTHrP is up-regulated by hypoxia in a HIF (hypoxia-inducible factor)-1α and HIF-2α-dependent manner. Using recombinant PTHrP, siRNA-mediated depletion of endogenous PTHrP and by blocking signalling through its receptor [PTHR1 (PTHrP receptor 1)], we show that hypoxia-induced PTHrP is a positive regulator of the key cartilage transcription factor SOX9 [SRY (sex determining region on the Y chromosome)-box 9], leading to increased COL2A1 (collagen type II, α1) expression. Our findings thus identify PTHrP as a potential factor for cartilage repair therapies through its ability to promote the differentiated HAC phenotype.
authors.affiliation: Kennedy Institute of Rheumatology, University of Oxford, 65 Aspenlea Road, London W6 8LH, UK.
authors.forename: Michele
authors.initials: M
authors.lastname: Pelosi
authors.forename: Stefano
authors.initials: S
authors.lastname: Lazzarano
authors.forename: Brendan L
authors.initials: BL
authors.lastname: Thoms
authors.forename: Chris L
authors.initials: CL
authors.lastname: Murphy
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology; D015415:Biomarkers / Q000378:metabolism; D002358:Cartilage, Articular / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D002454:Cell Differentiation / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D002478:Cells, Cultured; D002648:Child; D019902:Chondrocytes / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006984:Hypertrophy / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology; D008297:Male; D008875:Middle Aged; D044162:Parathyroid Hormone-Related Protein / Q000172:deficiency / Q000235:genetics / Q000494:pharmacology / Q000502:physiology*; D010641:Phenotype; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D055758:SOX9 Transcription Factor / Q000502:physiology; D055815:Young Adult; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D015415:Biomarkers; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D044162:Parathyroid Hormone-Related Protein; D034741:RNA, Small Interfering; D011994:Recombinant Proteins; D055758:SOX9 Transcription Factor; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C527932:SOX9 protein, human