title: Proline-rich tyrosine kinase 2 regulates osteoprogenitor cells and bone formation, and offers an anabolic treatment approach for osteoporosis.
abstract: 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.
authors.affiliation: Pfizer Global Research and Development, Groton, CT 06340, USA. leonard.buckbinder@pfizer.com
authors.forename: Leonard
authors.initials: L
authors.lastname: Buckbinder
authors.forename: David T
authors.initials: DT
authors.lastname: Crawford
authors.forename: Hong
authors.initials: H
authors.lastname: Qi
authors.forename: Hua Zhu
authors.initials: HZ
authors.lastname: Ke
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Olson
authors.forename: Kelly R
authors.initials: KR
authors.lastname: Long
authors.forename: Peter C
authors.initials: PC
authors.lastname: Bonnette
authors.forename: Amy P
authors.initials: AP
authors.lastname: Baumann
authors.forename: John E
authors.initials: JE
authors.lastname: Hambor
authors.forename: William A
authors.initials: WA
authors.lastname: Grasser
authors.forename: Lydia C
authors.initials: LC
authors.lastname: Pan
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Owen
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Luzzio
authors.forename: Catherine A
authors.initials: CA
authors.lastname: Hulford
authors.forename: David F
authors.initials: DF
authors.lastname: Gebhard
authors.forename: Vishwas M
authors.initials: VM
authors.lastname: Paralkar
authors.forename: Hollis A
authors.initials: HA
authors.lastname: Simmons
authors.forename: John C
authors.initials: JC
authors.lastname: Kath
authors.forename: W Gregory
authors.initials: WG
authors.lastname: Roberts
authors.forename: Steven L
authors.initials: SL
authors.lastname: Smock
authors.forename: Angel
authors.initials: A
authors.lastname: Guzman-Perez
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Brown
authors.forename: Mei
authors.initials: M
authors.lastname: Li
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D051418:Focal Adhesion Kinase 2