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Enhancement of osteoclastic bone resorption and suppression of osteoblastic bone formation in response to reduced mechanical stress do not occur in the absence of osteopontin.

Ishijima M, Rittling SR, Yamashita T, Tsuji K, Kurosawa H, Nifuji A, Denhardt DT, Noda M - J. Exp. Med. (2001)

Bottom Line: However, no molecule involved in the mechanisms underlying this phenomenon has been identified to date.Osteopontin (OPN) is one of the major noncollagenous proteins in bone matrix, but its function in mediating physical-force effects on bone in vivo has not been known.Analysis of the mechanisms of OPN deficiency-dependent reduction in bone on the cellular basis resulted in two unexpected findings.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101-0062, Japan.

ABSTRACT
Reduced mechanical stress to bone in bedridden patients and astronauts leads to bone loss and increase in fracture risk which is one of the major medical and health issues in modern aging society and space medicine. However, no molecule involved in the mechanisms underlying this phenomenon has been identified to date. Osteopontin (OPN) is one of the major noncollagenous proteins in bone matrix, but its function in mediating physical-force effects on bone in vivo has not been known. To investigate the possible requirement for OPN in the transduction of mechanical signaling in bone metabolism in vivo, we examined the effect of unloading on the bones of OPN(-/-) mice using a tail suspension model. In contrast to the tail suspension-induced bone loss in wild-type mice, OPN(-/-) mice did not lose bone. Elevation of urinary deoxypyridinoline levels due to unloading was observed in wild-type but not in OPN(-/-) mice. Analysis of the mechanisms of OPN deficiency-dependent reduction in bone on the cellular basis resulted in two unexpected findings. First, osteoclasts, which were increased by unloading in wild-type mice, were not increased by tail suspension in OPN(-/-) mice. Second, measures of osteoblastic bone formation, which were decreased in wild-type mice by unloading, were not altered in OPN(-/-) mice. These observations indicate that the presence of OPN is a prerequisite for the activation of osteoclastic bone resorption and for the reduction in osteoblastic bone formation in unloaded mice. Thus, OPN is a molecule required for the bone loss induced by mechanical stress that regulates the functions of osteoblasts and osteoclasts.

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An unloading-induced reduction in osteoblastic activity in vivo does not occur in OPN−/− mice. (A and B) In the undecalcified sections of the proximal ends of the tibiae, (A) BFR and (B) MAR at 350–600 μm distal to the growth plate in the metaphyseal region was measured as described in Materials and Methods. The mice were injected intraperitoneally with calcein at 4 mg/kg 4 and 2 d before killing at 2 wk. Data are expressed as means and standard errors for six bones from each of the wild-type and OPN−/− mice groups. *Statistically significant difference from respective control (P < 0.05). (C) Calcein double-labeled surfaces of the bones at the ends of the tibiae after tail suspension (Susp) or loading (Load) in wild-type or OPN−/− mice. Arrows indicate the lines of calcein labeling (light green) used to obtain data shown in A and B.
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Figure 4: An unloading-induced reduction in osteoblastic activity in vivo does not occur in OPN−/− mice. (A and B) In the undecalcified sections of the proximal ends of the tibiae, (A) BFR and (B) MAR at 350–600 μm distal to the growth plate in the metaphyseal region was measured as described in Materials and Methods. The mice were injected intraperitoneally with calcein at 4 mg/kg 4 and 2 d before killing at 2 wk. Data are expressed as means and standard errors for six bones from each of the wild-type and OPN−/− mice groups. *Statistically significant difference from respective control (P < 0.05). (C) Calcein double-labeled surfaces of the bones at the ends of the tibiae after tail suspension (Susp) or loading (Load) in wild-type or OPN−/− mice. Arrows indicate the lines of calcein labeling (light green) used to obtain data shown in A and B.

Mentions: Bone loss occurs as the result of an imbalance between bone resorption and bone formation. This imbalance could result from a relative increase of osteoclastic activity and/or a relative decrease in osteoblastic activity. Therefore, in addition to the analyses on osteoclastic aspects, we also examined the effects of OPN deficiency on unloading-induced bone loss with respect to osteoblastic features by using calcein double labeling. In loaded mice, basal levels of bone formation rate (BFR) and mineral apposition rate (MAR) were similar regardless of the genotypes (Fig. 4A and Fig. B) based on the analyses of calcein labeling (Fig. 4 C). In contrast to the reduction in BFR and MAR in wild-type mice after unloading (∼50 and 30%, respectively, P < 0.05; Fig. 4A and Fig. B), no alteration in BFR and MAR was observed in OPN−/− mice after unloading (Fig. 4A and Fig. B).


Enhancement of osteoclastic bone resorption and suppression of osteoblastic bone formation in response to reduced mechanical stress do not occur in the absence of osteopontin.

Ishijima M, Rittling SR, Yamashita T, Tsuji K, Kurosawa H, Nifuji A, Denhardt DT, Noda M - J. Exp. Med. (2001)

An unloading-induced reduction in osteoblastic activity in vivo does not occur in OPN−/− mice. (A and B) In the undecalcified sections of the proximal ends of the tibiae, (A) BFR and (B) MAR at 350–600 μm distal to the growth plate in the metaphyseal region was measured as described in Materials and Methods. The mice were injected intraperitoneally with calcein at 4 mg/kg 4 and 2 d before killing at 2 wk. Data are expressed as means and standard errors for six bones from each of the wild-type and OPN−/− mice groups. *Statistically significant difference from respective control (P < 0.05). (C) Calcein double-labeled surfaces of the bones at the ends of the tibiae after tail suspension (Susp) or loading (Load) in wild-type or OPN−/− mice. Arrows indicate the lines of calcein labeling (light green) used to obtain data shown in A and B.
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Related In: Results  -  Collection

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Figure 4: An unloading-induced reduction in osteoblastic activity in vivo does not occur in OPN−/− mice. (A and B) In the undecalcified sections of the proximal ends of the tibiae, (A) BFR and (B) MAR at 350–600 μm distal to the growth plate in the metaphyseal region was measured as described in Materials and Methods. The mice were injected intraperitoneally with calcein at 4 mg/kg 4 and 2 d before killing at 2 wk. Data are expressed as means and standard errors for six bones from each of the wild-type and OPN−/− mice groups. *Statistically significant difference from respective control (P < 0.05). (C) Calcein double-labeled surfaces of the bones at the ends of the tibiae after tail suspension (Susp) or loading (Load) in wild-type or OPN−/− mice. Arrows indicate the lines of calcein labeling (light green) used to obtain data shown in A and B.
Mentions: Bone loss occurs as the result of an imbalance between bone resorption and bone formation. This imbalance could result from a relative increase of osteoclastic activity and/or a relative decrease in osteoblastic activity. Therefore, in addition to the analyses on osteoclastic aspects, we also examined the effects of OPN deficiency on unloading-induced bone loss with respect to osteoblastic features by using calcein double labeling. In loaded mice, basal levels of bone formation rate (BFR) and mineral apposition rate (MAR) were similar regardless of the genotypes (Fig. 4A and Fig. B) based on the analyses of calcein labeling (Fig. 4 C). In contrast to the reduction in BFR and MAR in wild-type mice after unloading (∼50 and 30%, respectively, P < 0.05; Fig. 4A and Fig. B), no alteration in BFR and MAR was observed in OPN−/− mice after unloading (Fig. 4A and Fig. B).

Bottom Line: However, no molecule involved in the mechanisms underlying this phenomenon has been identified to date.Osteopontin (OPN) is one of the major noncollagenous proteins in bone matrix, but its function in mediating physical-force effects on bone in vivo has not been known.Analysis of the mechanisms of OPN deficiency-dependent reduction in bone on the cellular basis resulted in two unexpected findings.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular Pharmacology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 101-0062, Japan.

ABSTRACT
Reduced mechanical stress to bone in bedridden patients and astronauts leads to bone loss and increase in fracture risk which is one of the major medical and health issues in modern aging society and space medicine. However, no molecule involved in the mechanisms underlying this phenomenon has been identified to date. Osteopontin (OPN) is one of the major noncollagenous proteins in bone matrix, but its function in mediating physical-force effects on bone in vivo has not been known. To investigate the possible requirement for OPN in the transduction of mechanical signaling in bone metabolism in vivo, we examined the effect of unloading on the bones of OPN(-/-) mice using a tail suspension model. In contrast to the tail suspension-induced bone loss in wild-type mice, OPN(-/-) mice did not lose bone. Elevation of urinary deoxypyridinoline levels due to unloading was observed in wild-type but not in OPN(-/-) mice. Analysis of the mechanisms of OPN deficiency-dependent reduction in bone on the cellular basis resulted in two unexpected findings. First, osteoclasts, which were increased by unloading in wild-type mice, were not increased by tail suspension in OPN(-/-) mice. Second, measures of osteoblastic bone formation, which were decreased in wild-type mice by unloading, were not altered in OPN(-/-) mice. These observations indicate that the presence of OPN is a prerequisite for the activation of osteoclastic bone resorption and for the reduction in osteoblastic bone formation in unloaded mice. Thus, OPN is a molecule required for the bone loss induced by mechanical stress that regulates the functions of osteoblasts and osteoclasts.

Show MeSH
Related in: MedlinePlus