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.

Recent advances in the understanding of molecular mechanisms of cartilage degeneration, synovitis and subchondral bone changes in osteoarthritis

“…The abnormality observed in Ihh-/-mice is an increase in the fraction of chondrocytes which are post-mitotic, hypertrophic chondrocytes. This abnormality results from immature chondrocytes because Ihh-/-cartilage fails to synthesize parathyroid hormone-related protein (PTHrP) that keep chondrocytes in the proliferative phase and correlate with chondrocyte phenotype, specifically decrease expression of SOX9 leading to increased COL2A1 (collagen type II, α1) expression (41,42). Ihh is a critical and possible direct regulator of joint development.…”

Stearic acid induces proinflammatory cytokine production partly through activation of lactate-HIF1α pathway in chondrocytes

“…Obesity-induced metabolites regulate proinflammatory cytokine production through a large sum of transcription factors, like NF-κB 13 , forkhead box-containing protein O subfamily-1 7 , hypoxia-inducible factors (HIFs) 14 15 , etc. HIFs are composed of two dimeric subunits: an oxygen-sensitive α subunit (HIF1α or HIF2α) and a ubiquitously and constitutively expressed β subunit (HIF1β) 16 .…”

Identification of a potential gene target for osteoarthritis based on bioinformatics analyses

“…KEGG annotation entries existed in at least four datasets (dark blue columns of bars indicate) according to the annotation statistics most patients with OA tend to be older [5]. Second, chondrocytes and synovial tissues can produce PTLHL directly [38,39]. Therefore, in the pathological state of OA, chondrocytes and synovial tissues may secrete more PTHLH to maintain their own cell activity (Fig.…”