Independent impairment of osteoblast and osteoclast differentiation in klotho mouse exhibiting low-turnover osteopenia.
We recently identified a new gene, klotho, which is involved in the suppression of multiple aging phenotypes. The mouse homozygous for a disruption of the klotho locus (kl/kl) exhibited multiple pathological conditions resembling human aging. Histomorphometric analysis revealed low-turnover osteopenia in kl/kl mice. The decrease in bone formation exceeded that of bone resorption, resulting in a net bone loss. The number of osteoblast progenitors determined by ex vivo bone marrow cultures was reduced in kl/kl mice. In addition, cultured osteoblastic cells derived from kl/kl mice showed lower alkaline phosphatase activity and matrix nodule formation than those from wild-type mice. Osteoclastogenesis in the coculture of marrow cells and osteoblastic cells was decreased only when marrow cells originated from kl/kl mice independently of the origin of osteoblastic cells. We also found that the expression of osteoprotegerin, an osteoclastogenesis inhibitor, was significantly upregulated in kl/kl mice. We conclude that a defect in the klotho gene expression causes the independent impairment of both osteoblast and osteoclast differentiation, leading to low-turnover osteopenia. Because this state represents a characteristic feature of senile osteoporosis in humans, kl/kl mice can be regarded as a useful model for investigating cellular and molecular mechanisms of age-related bone loss.
Kawaguchi
H
H
Department of Orthopaedic Surgery, Faculty of Medicine, University of Tokyo, Tokyo 113-8655, Japan. kawaguchi-ort@h.u-tokyo.edu
Manabe
N
N
Miyaura
C
C
Chikuda
H
H
Nakamura
K
K
Kuro-o
M
M
D000375:Aging / Q000235:genetics; D000818:Animals; D015519:Bone Density / Q000235:genetics; D001851:Bone Diseases, Metabolic / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology* / Q000503:physiopathology; D001854:Bone Marrow Cells / Q000473:pathology; D019485:Bone Morphogenetic Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology; D002118:Calcium / Q000097:blood / Q000652:urine; D002454:Cell Differentiation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D005966:Glucuronidase; D000090265:Klotho Proteins; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008822:Mice, Transgenic; D010006:Osteoblasts / Q000473:pathology*; D010010:Osteoclasts / Q000473:pathology*; D010641:Phenotype; D012333:RNA, Messenger / Q000096:biosynthesis; D011859:Radiography; D013234:Stem Cells / Q000473:pathology
D019485:Bone Morphogenetic Proteins; D008565:Membrane Proteins; D012333:RNA, Messenger; D005966:Glucuronidase; D000090265:Klotho Proteins; D002118:Calcium