title: MKP1-dependent PTH modulation of bone matrix mineralization in female mice is osteoblast maturation stage specific and involves P-ERK and P-p38 MAPKs.
abstract: Limited information is available on the role of MAPK phosphatase 1 (MKP1) signaling in osteoblasts. We have recently reported distinct roles for MKP1 during osteoblast proliferation, differentiation, and skeletal responsiveness to parathyroid hormone (PTH). As MKP1 regulates the phosphorylation status of MAPKs, we investigated the involvement of P-ERK and P-p38 MAPKs in MKP1 knockout (KO) early and mature osteoblasts with respect to mineralization and PTH response. Calvarial osteoblasts from 9-14-week-old WT and MKP1 KO male and female mice were examined. Western blot analysis revealed downregulation and sustained expressions of P-ERK and P-p38 with PTH treatment in differentiated osteoblasts derived from KO males and females respectively. Exposure of early osteoblasts to p38 inhibitor, SB203580 (S), markedly inhibited mineralization in WT and KO osteoblasts from both genders as determined by von Kossa assay. In osteoblasts from males, ERK inhibitor U0126 (U), not p38 inhibitor (S), prevented the inhibitory effects of PTH on mineralization in early or mature osteoblasts. In osteoblasts from KO females, PTH sustained mineralization in early osteoblasts and decreased mineralization in mature cells. This effect of PTH was attenuated by S in early osteoblasts and by U in mature KO cells. Changes in matrix Gla protein expression with PTH in KO osteoblasts did not correlate with mineralization, indicative of MKP1-dependent additional mechanisms essential for PTH action on osteoblast mineralization. We conclude that PTH regulation of osteoblast mineralization in female mice is maturation stage specific and involves MKP1 modulation of P-ERK and P-p38 MAPKs.
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, Wayne State University School of Medicine, 1107 Elliman Clinical Research Building, 421 East Canfield Avenue, Detroit, Michigan 48201, USA.
authors.forename: Chandrika D
authors.initials: CD
authors.lastname: Mahalingam
authors.forename: Bharat Reddy
authors.initials: BR
authors.lastname: Sampathi
authors.forename: Sonali
authors.initials: S
authors.lastname: Sharma
authors.forename: Tanuka
authors.initials: T
authors.lastname: Datta
authors.forename: Varsha
authors.initials: V
authors.lastname: Das
authors.forename: Abdul B
authors.initials: AB
authors.lastname: Abou-Samra
authors.forename: Nabanita S
authors.initials: NS
authors.lastname: Datta
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002113:Calcification, Physiologic / Q000187:drug effects / Q000502:physiology*; D002454:Cell Differentiation / Q000187:drug effects; D015536:Down-Regulation; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009570:Nitriles / Q000494:pharmacology; D010006:Osteoblasts / Q000187:drug effects / Q000378:metabolism*; D010281:Parathyroid Hormone / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: D002070:Butadienes; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009570:Nitriles; D010281:Parathyroid Hormone; D011725:Pyridines; C113580:U 0126; D048049:Extracellular Signal-Regulated MAP Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1; C093642:SB 203580