Bone morphogenetic proteins signal via SMAD and mitogen-activated protein (MAP) kinase pathways at distinct times during osteoclastogenesis.
To investigate the role of bone morphogenetic protein (BMP) signaling in osteoclastogenesis in vivo, we eliminated BMPRII in osteoclasts by creating a BMPRII(fl/fl);lysM-Cre mouse strain. Conditional knock-out (cKO) mice are osteopetrotic when compared with WT controls due to a decrease in osteoclast activity. Bone marrow macrophages (BMMs) isolated from cKO mice are severely inhibited in their capacity to differentiate into mature osteoclasts in the presence of M-CSF and receptor activator of NF-κB (RANK) ligand. We also show that BMP noncanonical (MAPK) and canonical (SMAD) pathways are utilized at different stages of osteoclast differentiation. BMP2 induces p38 phosphorylation in pre-fusion osteoclasts and increases SMAD phosphorylation around osteoclast precursor fusion. Phosphorylation of MAPKs was decreased in differentiated BMMs from cKO animals. Treating BMMs with the SMAD inhibitor dorsomorphin confirms the requirement for the canonical pathway around the time of fusion. These results demonstrate the requirement for BMP signaling in osteoclasts for proper bone homeostasis and also explore the complex signaling mechanisms employed by BMP signaling during osteoclast differentiation.
From the Departments of Diagnostic and Biological Sciences.
Aaron
A
Broege
Lan
L
Pham
Eric D
ED
Jensen
Ann
A
Emery
Tsang-Hai
TH
Huang
Melissa
M
Stemig
Hideyuki
H
Beppu
Anna
A
Petryk
Michael
M
O'Connor
Kim
K
Mansky
Raj
R
Gopalakrishnan
D000818:Animals; D055396:Bone Morphogenetic Protein 2 / Q000235:genetics / Q000378:metabolism*; D052006:Bone Morphogenetic Protein Receptors, Type II / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D048049:Extracellular Signal-Regulated MAP Kinases / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis / Q000187:drug effects / Q000502:physiology; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D010010:Osteoclasts / Q000166:cytology / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D053245:RANK Ligand / Q000235:genetics / Q000378:metabolism; D051785:Smad Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
C525719:Bmp2 protein, mouse; D055396:Bone Morphogenetic Protein 2; D011720:Pyrazoles; D011743:Pyrimidines; D053245:RANK Ligand; D051785:Smad Proteins; C505689:Tnfsf11 protein, mouse; C516138:dorsomorphin; D048049:Extracellular Signal-Regulated MAP Kinases; C498219:Bmpr2 protein, mouse; D052006:Bone Morphogenetic Protein Receptors, Type II
BMPRII; Bone; Bone Morphogenetic Protein (BMP); Conditional Deletion; MAP Kinases (MAPKs); Osteoclast; Signal Transduction