A dual-specific macrophage colony-stimulating factor antagonist of c-FMS and αvβ3 integrin for osteoporosis therapy

PLoS Biology
Yuval ZurNiv Papo

Abstract

There is currently a demand for new highly efficient and specific drugs to treat osteoporosis, a chronic bone disease affecting millions of people worldwide. We have developed a combinatorial strategy for engineering bispecific inhibitors that simultaneously target the unique combination of c-FMS and αvβ3 integrin, which act in concert to facilitate bone resorption by osteoclasts. Using functional fluorescence-activated cell sorting (FACS)-based screening assays of random mutagenesis macrophage colony-stimulating factor (M-CSF) libraries against c-FMS and αvβ3 integrin, we engineered dual-specific M-CSF mutants with high affinity to both receptors. These bispecific mutants act as functional antagonists of c-FMS and αvβ3 integrin activation and hence of osteoclast differentiation in vitro and osteoclast activity in vivo. This study thus introduces a versatile platform for the creation of new-generation therapeutics with high efficacy and specificity for osteoporosis and other bone diseases. It also provides new tools for studying molecular mechanisms and the cell signaling pathways that mediate osteoclast differentiation and function.

References

Feb 1, 1996·Journal of Molecular Graphics·W HumphreyK Schulten
Nov 12, 1996·Biochemical and Biophysical Research Communications·P DengC W Rettenmier
Mar 1, 1996·Drug Safety : an International Journal of Medical Toxicology and Drug Experience·S Adami, N Zamberlan
Apr 21, 1999·International Journal of Cancer. Journal International Du Cancer·C MagnussonI Persson
Feb 23, 2000·The Journal of Clinical Investigation·K P McHughS L Teitelbaum
May 10, 2000·The Journal of Biological Chemistry·E F PlowJ W Smith
Aug 10, 2000·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·S TakeshitaA Kudo
Sep 1, 2000·Science·S L Teitelbaum
Jul 27, 2001·The Breast Journal·L PantanowitzJ L Fraser
Jan 24, 2002·The Journal of Experimental Medicine·Nacksung KimYongwon Choi
Aug 13, 2002·The Journal of Biological Chemistry·Norihiro IshidaTatsuo Takeya
Nov 11, 2003·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·Katie L StoneUNKNOWN Osteoporotic Fractures Research Group
May 26, 2004·Biochemical Society Transactions·J Takagi
Jun 4, 2005·Journal of Bone and Mineral Research : the Official Journal of the American Society for Bone and Mineral Research·L J MeltonB L Riggs
Jun 28, 2005·Nucleic Acids Research·Dina Schneidman-DuhovnyHaim J Wolfson
Oct 8, 2005·Journal of Computational Chemistry·David Van Der SpoelHerman J C Berendsen
Mar 21, 2006·European Journal of Cell Biology·Pierre JurdicOlivier Destaing
Apr 8, 2006·The International Journal of Biochemistry & Cell Biology·Caryn L ElsegoodLe T Duong
Sep 20, 2006·Osteoporosis International : a Journal Established As Result of Cooperation Between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA·O Johnell, J A Kanis
Apr 11, 2007·The Journal of Biological Chemistry·Roberta FaccioF Patrick Ross
Sep 28, 2007·Molecular Biology of the Cell·Anne ChabadelFrédéric Saltel
Nov 28, 2007·Annual Review of Pathology·Deborah V Novack, Steven L Teitelbaum
Apr 16, 2010·Annals of the New York Academy of Sciences·Wei Zou, Steven L Teitelbaum
Aug 21, 2012·Nature Structural & Molecular Biology·Jonathan ElegheertSavvas N Savvides
Aug 13, 2013·Biological & Pharmaceutical Bulletin·Naoto OkadaKazuo Minakuchi
Jan 28, 2014·Acta Orthopaedica·Jörg Schilcher, Per Aspenberg

❮ Previous
Next ❯

Citations

Feb 1, 2019·International Journal of Molecular Sciences·Abdul QadirAirong Qian
Jul 3, 2020·Journal of Orthopaedic Surgery and Research·Jianbiao LinZhenqi Ding
Sep 26, 2020·Scientific Reports·S Furquan AhmadAndrew W Horne
Apr 13, 2019·Cellular & Molecular Biology Letters·Liang SunShu Meng
Oct 25, 2020·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Tal TilayovNiv Papo
May 25, 2021·Immunological Reviews·Alicia BellomoMarc Bajénoff
Aug 10, 2021·Frontiers in Pharmacology·Shan-Shan LiDai-Feng Li

❮ Previous
Next ❯

Methods Mentioned

BETA
GTPase
flow cytometry
size exclusion chromatography
surface plasmon resonance
PCR
ELISA
enzyme linked immunosorbent assay
chip
fluorescence-activated cell sorting
circular dichroism

Software Mentioned

GraphPad Prism
Gromacs
Operetta
PatchDock
ImageJ
VMD
PyMOL Molecular Graphics System

Related Concepts

Related Feeds

Adhesion Molecules in Health and Disease

Cell adhesion molecules are a subset of cell adhesion proteins located on the cell surface involved in binding with other cells or with the extracellular matrix in the process called cell adhesion. In essence, cell adhesion molecules help cells stick to each other and to their surroundings. Cell adhesion is a crucial component in maintaining tissue structure and function. Discover the latest research on adhesion molecule and their role in health and disease here.