title: Mechanism of parathyroid hormone-mediated suppression of calcification markers in human intervertebral disc cells.
abstract: In degenerative intervertebral discs (IVD), type X collagen (COL X) expression (associated with hypertrophic differentiation) and calcification has been demonstrated. Suppression of COL X expression and calcification during disc degeneration can be therapeutic. In the present study we investigated the potential of human parathyroid hormone 1-34 (PTH) in suppressing indicators of calcification potential (alkaline phosphatase (ALP), Ca(2+), inorganic phosphate (Pi)), and COL X expression. Further, we sought to elucidate the mechanism of PTH action in annulus fibrosus (AF) and nucleus pulposus (NP) cells from human lumbar IVDs with moderate to advanced degeneration. Mitogen activated protein kinase (MAPK) signalling and alterations in the markers of calcification potential were analysed. PTH increased type II collagen (COL II) expression in AF (~200 %) and NP cells (~163 %) and decreased COL X levels both in AF and NP cells (~75 %). These changes in the expression of collagens were preceded by MAPK phosphorylation, which was increased in both AF and NP cells by PTH after 30 min. MAPK signalling inhibitor U0126 and protein kinase-A inhibitor H-89 DCH attenuated PTH stimulated COL II expression in both cell types. PTH decreased ALP activity and increased Ca(2+) release only in NP cells. The present study demonstrates that PTH can potentially retard IVD degeneration by stimulating matrix synthesis and suppressing markers of calcification potential in degenerated disc cells via both MAPK and PKA signalling pathways. Inhibition of further mineral deposition may therefore be a viable therapeutic option for improving the status of degenerating discs.
authors: SMBD-Jewish General Hospital, Lady Davis Institute for Medical Research, Montreal, QC, Canada.
authors: P
authors: P
authors: Madiraju
authors: R
authors: R
authors: Gawri
authors: H
authors: H
authors: Wang
authors: J
authors: J
authors: Antoniou
authors: F
authors: F
authors: Mwale
mesh_terms: D000328:Adult; D000368:Aged; D000469:Alkaline Phosphatase / Q000378:metabolism; D015415:Biomarkers / Q000378:metabolism; D002070:Butadienes / Q000494:pharmacology; D002113:Calcification, Physiologic / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D024043:Collagen Type II / Q000235:genetics / Q000378:metabolism; D024121:Collagen Type X / Q000235:genetics / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D005110:Extracellular Space / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D007403:Intervertebral Disc / Q000166:cytology* / Q000187:drug effects* / Q000201:enzymology; D007546:Isoquinolines / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008875:Middle Aged; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D009570:Nitriles / Q000494:pharmacology; D010281:Parathyroid Hormone / Q000494:pharmacology*; D044168:Receptor, Parathyroid Hormone, Type 1 / Q000378:metabolism; D055758:SOX9 Transcription Factor / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D015415:Biomarkers; D002070:Butadienes; D024043:Collagen Type II; D024121:Collagen Type X; D007546:Isoquinolines; D009570:Nitriles; C470125:PTH protein, human; D010281:Parathyroid Hormone; D044168:Receptor, Parathyroid Hormone, Type 1; D055758:SOX9 Transcription Factor; C527932:SOX9 protein, human; D013449:Sulfonamides; C113580:U 0126; D017868:Cyclic AMP-Dependent Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; D000469:Alkaline Phosphatase; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D002118:Calcium