title: Mitogen-activated protein kinase phosphatase 1 regulates bone mass, osteoblast gene expression, and responsiveness to parathyroid hormone.
abstract: Parathyroid hormone (PTH) signaling via PTH 1 receptor (PTH1R) involves mitogen-activated protein kinase (MAPK) pathways. MAPK phosphatase 1 (MKP1) dephosphorylates and inactivates MAPKs in osteoblasts, the bone-forming cells. We previously showed that PTH1R activation in differentiated osteoblasts upregulates MKP1 and downregulates pERK1/2-MAPK and cyclin D1. In this study, we evaluated the skeletal phenotype of Mkp1 knockout (KO) mice and the effects of PTH in vivo and in vitro. Microcomputed tomography analysis of proximal tibiae and distal femora from 12-week-old Mkp1 KO female mice revealed osteopenic phenotype with significant reduction (8-46%) in bone parameters compared with wild-type (WT) controls. Histomorphometric analysis showed decreased trabecular bone area in KO females. Levels of serum osteocalcin (OCN) were lower and serum tartrate-resistant acid phosphatase 5b (TRAP5b) was higher in KO animals. Treatment of neonatal mice with hPTH (1-34) for 3 weeks showed attenuated anabolic responses in the distal femora of KO mice compared with WT mice. Primary osteoblasts derived from KO mice displayed delayed differentiation determined by alkaline phosphatase activity, and reduced expressions of Ocn and Runx2 genes associated with osteoblast maturation and function. Cells from KO females exhibited attenuated PTH response in mineralized nodule formation in vitro. Remarkably, this observation was correlated with decreased PTH response of matrix Gla protein expression. Expressions of pERK1/2 and cyclin D1 were inhibited dramatically by PTH in differentiated osteoblasts from WT mice but much less in osteoblasts from Mkp1 KO mice. In conclusion, MKP1 is important for bone homeostasis, osteoblast differentiation and skeletal responsiveness to PTH.
authors.affiliation: Division of Endocrinology, Department of Internal Medicine, Wayne State University School of Medicine, Detroit, Michigan 48201, USA.
authors.forename: Chandrika D
authors.initials: CD
authors.lastname: Mahalingam
authors.forename: Tanuka
authors.initials: T
authors.lastname: Datta
authors.forename: Rashmi V
authors.initials: RV
authors.lastname: Patil
authors.forename: Jaclynn
authors.initials: J
authors.lastname: Kreider
authors.forename: R Daniel
authors.initials: RD
authors.lastname: Bonfil
authors.forename: Keith L
authors.initials: KL
authors.lastname: Kirkwood
authors.forename: Steven A
authors.initials: SA
authors.lastname: Goldstein
authors.forename: Abdul B
authors.initials: AB
authors.lastname: Abou-Samra
authors.forename: Nabanita S
authors.initials: NS
authors.lastname: Datta
mesh_terms: D000135:Acid Phosphatase / Q000097:blood; D000818:Animals; D000831:Animals, Newborn; D015153:Blotting, Western; D001842:Bone and Bones / Q000033:anatomy & histology / Q000187:drug effects / Q000378:metabolism*; D002454:Cell Differentiation / Q000187:drug effects; D002460:Cell Line; D002478:Cells, Cultured; D050659:Core Binding Factor Alpha 1 Subunit / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D054638:Dual Specificity Phosphatase 1 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007527:Isoenzymes / Q000097:blood; D008297:Male; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010006:Osteoblasts / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D015675:Osteocalcin / Q000097:blood / Q000235:genetics / Q000378:metabolism; D010281:Parathyroid Hormone / Q000494:pharmacology*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071681:Tartrate-Resistant Acid Phosphatase; D055114:X-Ray Microtomography
chemical_list: D050659:Core Binding Factor Alpha 1 Subunit; D007527:Isoenzymes; D010281:Parathyroid Hormone; C493716:Runx2 protein, mouse; D015675:Osteocalcin; D019938:Cyclin D1; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D000135:Acid Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase; D054638:Dual Specificity Phosphatase 1; C517020:Dusp1 protein, mouse