title: Endogenous prostaglandin E2 and insulin-like growth factor 1 can modulate the levels of parathyroid hormone receptor in human osteoarthritic osteoblasts.
abstract: Subchondral bone sclerosis may be important for the onset and/or progression of cartilage loss/damage in human osteoarthritis (OA). OA osteoblasts are resistant to parathyroid hormone (PTH) stimulation, which could explain bone sclerosis via the inhibition of PTH-dependent catabolism. Here, we investigated the molecular mechanism(s) responsible for reduced PTH-dependent cyclic adenosine monophosphate (cAMP) synthesis in OA subchondral osteoblasts. Although cholera toxin (CTX) increased basal cAMP formation in these cells, it failed to stimulate PTH-dependent cAMP synthesis, whereas pertussis toxin (PTX) did not inhibit basal cAMP, yet diminished PTH-dependent cAMP production. Binding of 125I-PTH indicated lower PTH receptor levels in OA than in normal osteoblasts (-50.5 +/- 9.5%). This could be attributed to either reduced expression of the PTH receptor (PTH-R) or altered recycling of existing pools of receptors. Reverse-transcription polymerase chain reaction (RT-PCR) analysis indicated decreased PTH-R messenger RNA (mRNA) levels in OA cells that were highly variable (ranging from -10% to -60%), a situation that reflects disease severity. Interestingly, OA osteoblasts produced more prostaglandin E2 (PGE2) than normal osteoblasts, and using naproxen, a cyclo-oxygenase inhibitor, increased PTH-dependent cAMP formation to a level similar to normal osteoblasts. Because heterologous desensitization can explain a decrease in PTH binding but cannot account for reduced PTH-R expression, we looked at the possible effect of insulin-like growth factor 1 (IGF-1) on this parameter. Blocking IGF-1 signaling with a neutralizing receptor antibody increased 125I-PTH binding in both normal and OA osteoblasts. Conversely, treatments with IGF-1 receptor (IGF-1R) antibody only slightly increased the levels of PTH-R mRNA whereas the addition of IGF-1 significantly reduced PTH-R mRNA levels (-24.1 +/- 7.1%), yet neither PGE2 nor naproxen modified PTH-R levels. These results suggest that both IGF-1 signaling and PGE2 formation repress PTH-dependent response in OA osteoblasts, a situation that can contribute to abnormal bone remodeling and bone sclerosis in OA.
authors.affiliation: Osteoarthritis Research Unit, H pital Notre-Dame, Centre Hospitalier de l'Université de Montréal, Québec, Canada.
authors.forename: G
authors.initials: G
authors.lastname: Hilal
authors.forename: F
authors.initials: F
authors.lastname: Massicotte
authors.forename: J
authors.initials: J
authors.lastname: Martel-Pelletier
authors.forename: J C
authors.initials: JC
authors.lastname: Fernandes
authors.forename: J P
authors.initials: JP
authors.lastname: Pelletier
authors.forename: D
authors.initials: D
authors.lastname: Lajeunesse
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D016723:Bone Remodeling / Q000502:physiology; D002478:Cells, Cultured; D002772:Cholera Toxin / Q000494:pharmacology; D000242:Cyclic AMP / Q000096:biosynthesis; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000096:biosynthesis / Q000502:physiology*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000502:physiology*; D008297:Male; D008875:Middle Aged; D009288:Naproxen / Q000494:pharmacology; D010003:Osteoarthritis / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D010281:Parathyroid Hormone / Q000378:metabolism / Q000494:pharmacology; D037342:Pertussis Toxin; D012333:RNA, Messenger / Q000096:biosynthesis; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors / Q000276:immunology; D018016:Receptors, Parathyroid Hormone / Q000096:biosynthesis* / Q000187:drug effects / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015290:Second Messenger Systems / Q000187:drug effects; D010566:Virulence Factors, Bordetella / Q000494:pharmacology
chemical_list: D016861:Cyclooxygenase Inhibitors; D010281:Parathyroid Hormone; D012333:RNA, Messenger; D018016:Receptors, Parathyroid Hormone; D010566:Virulence Factors, Bordetella; D009288:Naproxen; D007334:Insulin-Like Growth Factor I; D002772:Cholera Toxin; D000242:Cyclic AMP; D037342:Pertussis Toxin; D017526:Receptor, IGF Type 1; D015232:Dinoprostone