title: Endothelin-1 inhibits human osteoblastic cell differentiation: influence of connexin-43 expression level.
abstract: Gap junctional intercellular communication (GJIC) permits coordinated cellular activities during developmental and differentiation processes. In bone, the involvement of the gap junctional protein, connexin-43 (Cx43), and of GJIC in osteoblastic differentiation and mineralization of the extracellular matrix has been previously demonstrated. Former studies have shown that endothelin-1 (ET-1) was also implicated in the control of osteoblastic proliferation and differentiation. However, depending on the cellular models, ET-1 has been shown to decrease or increase osteoblastic differentiation markers. As no data were available on the ET-1 effect on GJIC and Cx43 expression in osteoblastic cells, we analyzed here the possible crosstalk between Cx43 and ET-1 in a human cell line (hFOB 1.19) which displays different Cx43 expression levels and phenotypes when cultured at 33.5 or 39 degrees C. The presence of ET-1 (10(-8) M) for 2-12 days of culture did not significantly alter the proliferation rate of hFOB cells whatever their phenotype. In contrast, ET-1 induced a differential inhibitory effect on the biochemical differentiation markers (alkaline phosphatase activity and osteocalcin expression) with a significant reduction in the differentiated phenotype at 39 degrees C, whereas no effects were measured at 33.5 degrees C. The inhibitory effect was linked to a decrease of GJIC and of Cx43 both at transcriptional and protein levels. Altogether, our results suggest that Cx43 expression level could influence the action of ET-1 on human osteoblastic cell differentiation. Our data also indicate that the gap junctional protein could play a pivotal role in the response of osteoblasts to mitogenic factors implicated in bone pathologies.
authors.affiliation: Department of Orthopaedics, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: Corinne
authors.initials: C
authors.lastname: Niger
authors.forename: Graziello
authors.initials: G
authors.lastname: Geneau
authors.forename: Céline
authors.initials: C
authors.lastname: Fiorini
authors.forename: Norah
authors.initials: N
authors.lastname: Defamie
authors.forename: Georges
authors.initials: G
authors.lastname: Pointis
authors.forename: Marc
authors.initials: M
authors.lastname: Mesnil
authors.forename: Laurent
authors.initials: L
authors.lastname: Cronier
mesh_terms: D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D018031:Connexin 43 / Q000378:metabolism*; D019332:Endothelin-1 / Q000494:pharmacology*; D017629:Gap Junctions / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D010006:Osteoblasts / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D044022:Receptor, Endothelin A / Q000378:metabolism
chemical_list: D018031:Connexin 43; D019332:Endothelin-1; D044022:Receptor, Endothelin A