title: Systemic injection of CK2.3, a novel peptide acting downstream of bone morphogenetic protein receptor BMPRIa, leads to increased trabecular bone mass.
abstract: Bone Morphogenetic Protein 2 (BMP2) regulates bone integrity by driving both osteogenesis and osteoclastogenesis. However, BMP2 as a therapeutic has significant drawbacks. We have designed a novel peptide CK2.3 that blocks the interaction of Casein Kinase 2 (CK2) with Bone Morphogenetic Protein Receptor type Ia (BMPRIa), thereby activating BMP signaling pathways in the absence of ligand. Here, we show that CK2.3 induced mineralization in primary osteoblast cultures isolated from calvaria and bone marrow stromal cells (BMSCs) of 8 week old mice. Further, systemic tail vein injections of CK2.3 in 8 week old mice resulted in increased bone mineral density (BMD) and mineral apposition rate (MAR). In situ immunohistochemistry of the femur found that CK2.3 injection induced phosphorylation of extracellular signal-related kinase (ERK), but not Smad in osteocytes and osteoblasts, suggesting that CK2.3 signaling occurred through Smad independent pathway. Finally mice injected with CK2.3 exhibited decreased osteoclast differentiation and osteoclast activity. These data indicate that the novel mimetic peptide CK2.3 activated BMPRIa downstream signaling to enhance bone formation without the increase in osteoclast activity that accompanies BMP 2 stimulation.
authors.affiliation: Department of Biological Sciences, University of Delaware, Newark, Delaware.
authors.forename: Hemanth
authors.initials: H
authors.lastname: Akkiraju
authors.forename: Jeremy
authors.initials: J
authors.lastname: Bonor
authors.forename: Kristine
authors.initials: K
authors.lastname: Olli
authors.forename: Chris
authors.initials: C
authors.lastname: Bowen
authors.forename: Beth
authors.initials: B
authors.lastname: Bragdon
authors.forename: Harold
authors.initials: H
authors.lastname: Coombs
authors.forename: Leah Rae
authors.initials: LR
authors.lastname: Donahue
authors.forename: Randall
authors.initials: R
authors.lastname: Duncan
authors.forename: Anja
authors.initials: A
authors.lastname: Nohe
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D015415:Biomarkers / Q000097:blood; D015519:Bone Density / Q000187:drug effects; D052005:Bone Morphogenetic Protein Receptors, Type I / Q000819:agonists*; D047390:Casein Kinase II / Q000037:antagonists & inhibitors*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D059630:Mesenchymal Stem Cells / Q000187:drug effects; D008810:Mice, Inbred C57BL; D010010:Osteoclasts / Q000187:drug effects; D010012:Osteogenesis / Q000187:drug effects*; D010455:Peptides / Q000494:pharmacology*; D012886:Skull / Q000187:drug effects; D051785:Smad Proteins / Q000378:metabolism
chemical_list: D015415:Biomarkers; D010455:Peptides; D051785:Smad Proteins; D047390:Casein Kinase II; D048049:Extracellular Signal-Regulated MAP Kinases; C498212:Bmpr1a protein, mouse; D052005:Bone Morphogenetic Protein Receptors, Type I
keywords: bone mineral density; bone morphogenetic protein; casein kinase 2; mimetic peptide; osteoporosis