Transgenic mice with OIP-1/hSca overexpression targeted to the osteoclast lineage develop an osteopetrosis bone phenotype.
Regulatory mechanisms operative in bone-resorbing osteoclasts are complex. We previously defined the Ly-6 gene family member OIP-1/hSca as an inhibitor of osteoclastogenesis in vitro; however, a role in skeletal development is unknown. In this study, we developed transgenic mice with OIP-1/hSca expression targeted to the osteoclast lineage that develop an osteopetrotic bone phenotype. Humeri from OIP-1 mice showed a significant increase in bone mineral density and bone mineral content. microCT analysis showed increased trabecular thickness and bone volume. OIP-1 mice have dense sclerotic cortical bone with absence of spongiosa and inadequate formation of marrow spaces compared to wild-type mice. Moreover, complete inhibition of osteoclasts and marrow cavities in calvaria suggests defective bone resorption in these mice. OIP-1 mouse bone marrow cultures demonstrated a significant decrease (41%) in osteoclast progenitors and inhibition (39%) of osteoclast differentiation/bone resorption. Western blot analysis further demonstrated suppression of TRAF-2, c-Fos, p-c-Jun, and NFATc1 levels in RANKL-stimulated osteoclast precursors derived from OIP-1 mice. Therefore, OIP-1 is an important physiological inhibitor of osteoclastogenesis and may have therapeutic value against bone loss in vivo.
Shanmugarajan
S
S
Children's Research Institute, Medical University of South Carolina, Charleston, SC 29425, USA.
Irie
K
K
Musselwhite
C
C
Key
L L
LL
Ries
W L
WL
Reddy
S V
SV
D000074183:ATPases Associated with Diverse Cellular Activities; D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism / Q000502:physiology*; D000818:Animals; D001854:Bone Marrow Cells / Q000473:pathology; D016723:Bone Remodeling / Q000502:physiology; D001862:Bone Resorption / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D001842:Bone and Bones / Q000000981:diagnostic imaging / Q000473:pathology / Q000503:physiopathology; D002454:Cell Differentiation; D002478:Cells, Cultured; D060588:LIM Domain Proteins; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000473:pathology; D010010:Osteoclasts / Q000502:physiology*; D010022:Osteopetrosis / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D010641:Phenotype; D046988:Proteasome Endopeptidase Complex; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000378:metabolism; D015398:Signal Transduction; D014057:Tomography, X-Ray Computed; D014157:Transcription Factors / Q000378:metabolism / Q000502:physiology*
D048868:Adaptor Proteins, Signal Transducing; D060588:LIM Domain Proteins; C092282:PSMC5 protein, human; D053246:Receptor Activator of Nuclear Factor-kappa B; D014157:Transcription Factors; D046988:Proteasome Endopeptidase Complex; D000074183:ATPases Associated with Diverse Cellular Activities