title: Intermittent PTH(1-34) signals through protein kinase A to regulate osteoprotegerin production in human periodontal ligament cells in vitro.
abstract: Periodontal ligament (PDL) cells have been associated with the regulation of periodontal repair processes by the differential expression of osteoprotegerin and RANKL in response to intermittent parathyroid hormone (PTH) resulting in a modified activity of bone-resorbing osteoclasts. Here, we examined the intracellular signaling pathways that PDL cells use to mediate the PTH(1-34) effect on osteoprotegerin production and hypothesized that those would be dependent on the cellular maturation stage. Two stages of confluence served as a model for cellular maturation of 5th passage human PDL cells from six donors. Intermittent PTH(1-34) (10(-12) M) and PTH(1-31), the latter lacking the protein kinase C (PKC) activating domain, induced a significant decrease of osteoprotegerin production in confluent cultures, whereas the signal-specific fragments PTH(3-34) and PTH(7-34), which both are unable to activate protein kinase A (PKA), had no effect. The addition of the PKA inhibitor H8 antagonized the PTH(1-34) effect, whereas the PKC inhibitor RO-32-0432 did not. In pre-confluent, less mature cultures, intermittent PTH(1-34) resulted in a significant increase of osteoprotegerin. Similar results were obtained when PTH(1-31) substituted for PTH(1-34) as opposed to a lack of an effect of PTH(3-34) and PTH(7-34). Likewise, in confluent cultures, H8 inhibited the PTH(1-34) effect in pre-confluent cultures contrasted by RO-32-0432 which had no effect. These findings indicate that PTH(1-34) signaling targeting osteoprotegerin production in PDL cells involves a PKA-dependent pathway. The PTH(1-34) effect is dependent on cell status, whereas intracellular signal transduction is not. Clinical trials will have to prove whether those in vitro data are of physiological relevance for interference strategies.
authors.affiliation: Dept. of Prosthodontics, Dental Clinic, University of Bonn, Bonn, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Kraus
authors.forename: Andreas
authors.initials: A
authors.lastname: Jäger
authors.forename: Nuersailike
authors.initials: N
authors.lastname: Abuduwali
authors.forename: James
authors.initials: J
authors.lastname: Deschner
authors.forename: Stefan
authors.initials: S
authors.lastname: Lossdörfer
mesh_terms: D000293:Adolescent; D018929:Cell Culture Techniques; D002648:Child; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000187:drug effects*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000494:pharmacology*; D007546:Isoquinolines / Q000494:pharmacology; D053244:Osteoprotegerin / Q000187:drug effects*; D010281:Parathyroid Hormone / Q000494:pharmacology; D010446:Peptide Fragments / Q000494:pharmacology; D010513:Periodontal Ligament / Q000166:cytology* / Q000378:metabolism; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D011758:Pyrroles / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects*; D019379:Teriparatide / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D007211:Indoles; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines; D053244:Osteoprotegerin; D010281:Parathyroid Hormone; D010446:Peptide Fragments; D011758:Pyrroles; C101312:parathyroid hormone (1-31); C058350:parathyroid hormone (7-34); D019379:Teriparatide; C085989:Ro 32-0432; C031617:parathyroid hormone (3-34); C053177:N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide; D017868:Cyclic AMP-Dependent Protein Kinases; D011493:Protein Kinase C