Deletion of the P2X7 nucleotide receptor reveals its regulatory roles in bone formation and resorption.
The P2X7 nucleotide receptor is an ATP-gated ion channel expressed widely in cells of hematopoietic origin. Our purpose was to explore the involvement of the P2X7 receptor in bone development and remodeling by characterizing the phenotype of mice genetically modified to disrupt the P2X7 receptor [knockout (KO)]. Femoral length did not differ between KO and wild-type (WT) littermates at 2 or 9 months of age, indicating that the P2X7 receptor does not regulate longitudinal bone growth. However, KO mice displayed significant reduction in total and cortical bone content and periosteal circumference in femurs, and reduced periosteal bone formation and increased trabecular bone resorption in tibias. Patch clamp recording confirmed expression of functional P2X7 receptors in osteoclasts from WT but not KO mice. Osteoclasts were present in vivo and formed in cultures of bone marrow from KO mice, indicating that this receptor is not essential for fusion of osteoclast precursors. Functional P2X7 receptors were also found in osteoblasts from WT but not KO mice, suggesting a direct role in bone formation. P2X7 receptor KO mice demonstrate a unique skeletal phenotype that involves deficient periosteal bone formation together with excessive trabecular bone resorption. Thus, the P2X7 receptor represents a novel therapeutic target for the management of skeletal disorders such as osteoporosis.
Ke
Hua Zhu
HZ
Pfizer Global Research and Development, Groton Laboratories, Connecticut 06340, USA. huazhu_ke@groton.Pfizer.com
Qi
Hong
H
Weidema
A Frederik
AF
Zhang
Qing
Q
Panupinthu
Nattapon
N
Crawford
D Todd
DT
Grasser
William A
WA
Paralkar
Vishwas M
VM
Li
Mei
M
Audoly
Laurent P
LP
Gabel
Christopher A
CA
Jee
Webster S S
WS
Dixon
S Jeffrey
SJ
Sims
Stephen M
SM
Thompson
David D
DD
D000818:Animals; D001846:Bone Development / Q000235:genetics*; D001854:Bone Marrow Cells / Q000166:cytology; D001862:Bone Resorption / Q000235:genetics*; D002478:Cells, Cultured; D005260:Female; D005269:Femur / Q000033:anatomy & histology / Q000254:growth & development / Q000473:pathology; D018507:Gene Expression Regulation, Developmental; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D010006:Osteoblasts / Q000502:physiology; D010010:Osteoclasts / Q000502:physiology; D018408:Patch-Clamp Techniques; D018048:Receptors, Purinergic P2 / Q000502:physiology*; D058486:Receptors, Purinergic P2X7; D014054:Tomography / Q000379:methods
C546469:P2rx7 protein, mouse; D018048:Receptors, Purinergic P2; D058486:Receptors, Purinergic P2X7