title: Osteocalcin attenuates T3- and increases vitamin D3-induced expression of MMP-13 in mouse osteoblasts.
abstract: Osteocalcin (OCN), the most abundant non-collagenous protein of the bone matrix, whose function is not fully understood, was recently suggested to act as endocrine factor regulating energy metabolism. Besides OCN, osteoblasts also express MMP-13, a matrix metallo-proteinase important for bone development and remodeling. Although differentially, both genes are regulated by 1,25-dihydroxy vitamin D3 (1,25D3) and T3, important hormones for bone metabolism. In mouse osteoblasts with a distinct differentiation status, T3 increases the expression of both proteins. By contrast, 1,25D3 stimulates the expression of MMP-13 but inhibits the expression of OCN in these cells. In humans, however, 1,25D3 upregulates both genes while T3 inhibits the OCN expression. Using northern blot hybridization we studied gene expression in the mouse osteoblastic cell line MC3T3-E1. We show that MMP-13 expression was strongly increased by T3 when the stimulation of OCN was low and, inversely, that the MMP-13 increase was low when T3 strongly stimulated the OCN expression. These findings suggest an interrelationship between OCN and MMP-13 expression. In fact, we observed that externally added OCN attenuated the T3 induced MMP-13 expression dose dependently and, furthermore, increased the 1,25D3 stimulated MMP-13 expression. Using a protein kinase A inhibitor we were able to show that this inhibitor mimics the effect of OCN suggesting a PKA dependent pathway to be involved in this regulatory process. We therefore hypothesize that OCN is a modulator of the hormonally regulated MMP-13 expression.
authors.affiliation: Ludwig Boltzmann Institute of Osteology at Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling. 4th Medical Department, Hanusch Hospital, Vienna, Austria.
authors.forename: Franz
authors.initials: F
authors.lastname: Varga
authors.forename: Monika
authors.initials: M
authors.lastname: Rumpler
authors.forename: Silvia
authors.initials: S
authors.lastname: Spitzer
authors.forename: Heidrun
authors.initials: H
authors.lastname: Karlic
authors.forename: Klaus
authors.initials: K
authors.lastname: Klaushofer
mesh_terms: D000818:Animals; D002117:Calcitriol / Q000502:physiology; D002417:Cattle; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D005786:Gene Expression Regulation; D007546:Isoquinolines / Q000494:pharmacology; D053509:Matrix Metalloproteinase 13 / Q000096:biosynthesis*; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism; D015675:Osteocalcin / Q000494:pharmacology / Q000502:physiology*; D013268:Stimulation, Chemical; D013449:Sulfonamides / Q000494:pharmacology; D014284:Triiodothyronine / Q000037:antagonists & inhibitors
chemical_list: D007546:Isoquinolines; D013449:Sulfonamides; D014284:Triiodothyronine; D015675:Osteocalcin; C043204:N-(2-guanidinoethyl)-5-isoquinolinesulfonamide; D017868:Cyclic AMP-Dependent Protein Kinases; D053509:Matrix Metalloproteinase 13; D002117:Calcitriol