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Systemic Injection of CK2.3, a Novel Peptide Acting Downstream of Bone Morphogenetic Protein Receptor BMPRIa, Leads to Increased Trabecular Bone Mass
Author(s) -
Akkiraju Hemanth,
Bonor Jeremy,
Olli Kristine,
Bowen Chris,
Bragdon Beth,
Coombs Harold,
Donahue Leah Rae,
Duncan Randall,
Nohe Anja
Publication year - 2015
Publication title -
journal of orthopaedic research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.041
H-Index - 155
eISSN - 1554-527X
pISSN - 0736-0266
DOI - 10.1002/jor.22752
Subject(s) - osteoclast , smad , chemistry , bone morphogenetic protein 2 , osteoblast , microbiology and biotechnology , bone mineral , medicine , endocrinology , bone morphogenetic protein , stromal cell , casein kinase 2 , signal transduction , phosphorylation , receptor , protein kinase a , osteoporosis , biology , biochemistry , cyclin dependent kinase 2 , gene , in vitro
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.© 2014 Orthopaedic Research Society. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:208–215, 2015.