Proline-rich tyrosine kinase 2 regulates osteoprogenitor cells and bone formation, and offers an anabolic treatment approach for osteoporosis.
Bone is accrued and maintained primarily through the coupled actions of bone-forming osteoblasts and bone-resorbing osteoclasts. Cumulative in vitro studies indicated that proline-rich tyrosine kinase 2 (PYK2) is a positive mediator of osteoclast function and activity. However, our investigation of PYK2-/- mice did not reveal evidence supporting an essential function for PYK2 in osteoclasts either in vivo or in culture. We find that PYK2-/- mice have high bone mass resulting from an unexpected increase in bone formation. Consistent with the in vivo findings, mouse bone marrow cultures show that PYK2 deficiency enhances differentiation and activity of osteoprogenitor cells, as does expressing a PYK2-specific short hairpin RNA or dominantly interfering proteins in human mesenchymal stem cells. Furthermore, the daily administration of a small-molecule PYK2 inhibitor increases bone formation and protects against bone loss in ovariectomized rats, an established preclinical model of postmenopausal osteoporosis. In summary, we find that PYK2 regulates the differentiation of early osteoprogenitor cells across species and that inhibitors of the PYK2 have potential as a bone anabolic approach for the treatment of osteoporosis.
Buckbinder
Leonard
L
Pfizer Global Research and Development, Groton, CT 06340, USA. leonard.buckbinder@pfizer.com
Crawford
David T
DT
Qi
Hong
H
Ke
Hua Zhu
HZ
Olson
Lisa M
LM
Long
Kelly R
KR
Bonnette
Peter C
PC
Baumann
Amy P
AP
Hambor
John E
JE
Grasser
William A
WA
Pan
Lydia C
LC
Owen
Thomas A
TA
Luzzio
Michael J
MJ
Hulford
Catherine A
CA
Gebhard
David F
DF
Paralkar
Vishwas M
VM
Simmons
Hollis A
HA
Kath
John C
JC
Roberts
W Gregory
WG
Smock
Steven L
SL
Guzman-Perez
Angel
A
Brown
Thomas A
TA
Li
Mei
M
D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000502:physiology; D002454:Cell Differentiation; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005260:Female; D051418:Focal Adhesion Kinase 2 / Q000502:physiology*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000502:physiology*; D010010:Osteoclasts / Q000502:physiology*; D010012:Osteogenesis / Q000502:physiology*; D010024:Osteoporosis / Q000628:therapy*; D010052:Ovariectomy; D051381:Rats; D017207:Rats, Sprague-Dawley
D004791:Enzyme Inhibitors; D051418:Focal Adhesion Kinase 2