Independent impairment of osteoblast and osteoclast differentiation in klotho mouse exhibiting low-turnover osteopenia
Hiroshi Kawaguchi, Noriyo Manabe, Chisato Miyaura, Hirotaka Chikuda, Kozo Nakamura, Makoto Kuro-o
Hiroshi Kawaguchi, Noriyo Manabe, Chisato Miyaura, Hirotaka Chikuda, Kozo Nakamura, Makoto Kuro-o
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Article

Independent impairment of osteoblast and osteoclast differentiation in klotho mouse exhibiting low-turnover osteopenia

Abstract

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.

Authors

Hiroshi Kawaguchi, Noriyo Manabe, Chisato Miyaura, Hirotaka Chikuda, Kozo Nakamura, Makoto Kuro-o

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Osteoclastogenesis in ex vivo bone marrow cell cultures (a) and in the c...
Osteoclastogenesis in ex vivo bone marrow cell cultures (a) and in the coculture of osteoblastic cells and bone marrow cells (b) from wild-type mice and kl/kl mice. (a) The number of TRAP-positive osteoclastic cells (top) and GM-CFU (middle) at 8 days of culture of bone marrow cells from 7-week-old wild-type or kl/kl mice. Data are expressed as mean (bars) ± SEM (error bars) for 8 and 6 wells per group, respectively. *Significantly different from wild-type cells (P < 0.01). The percentage of F4/80-positive monocyte macrophages in bone marrow cells was measured by flow cytometric analysis using FITC-labeled F4/80 (bottom). (b) The number of TRAP-positive osteoclastic cells formed at 8 days of coculture (top) and the pit area resorbed by osteoclastic cells by an additional 48 hours of culture on a dentine slice (bottom; percent of whole dentine). The origins (+ for wild-type mice and kl for kl/kl mice) of the cells are indicated as “Osteoblasts: marrow cells.” Data are expressed as mean (bars) ± SEM (error bars) for 8 wells per group. *Significantly different from wild-type cultures (P < 0.01).