Limits...
Nrf2 is required for normal postnatal bone acquisition in mice.

Kim JH, Singhal V, Biswal S, Thimmulappa RK, DiGirolamo DJ - Bone Res (2014)

Bottom Line: A large body of literature suggests that bone metabolism is susceptible to the ill effects of reactive species that accumulate in the body and cause cellular dysfunction.Despite the breadth of knowledge of both the function of Nrf2 and the effects of reactive species in bone metabolism, the direct role of Nrf2 in skeletal biology has yet to be thoroughly examined.Taken together, these studies suggest Nrf2 represents a key pathway in regulating bone metabolism, which may provide future therapeutic targets to treat osteoporosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health , Baltimore, MD, USA.

ABSTRACT
A large body of literature suggests that bone metabolism is susceptible to the ill effects of reactive species that accumulate in the body and cause cellular dysfunction. One of the body's front lines in defense against such damage is the transcription factor, Nrf2. This transcription factor regulates a plethora of antioxidant and cellular defense pathways to protect cells from such damage. Despite the breadth of knowledge of both the function of Nrf2 and the effects of reactive species in bone metabolism, the direct role of Nrf2 in skeletal biology has yet to be thoroughly examined. Thus, in the current study, we have examined the role of Nrf2 in postnatal bone metabolism in mice. Mice lacking Nrf2 (Nrf2(-/-)) exhibited a marked deficit in postnatal bone acquisition, which was most severe at 3 weeks of age when osteoblast numbers were 12-fold less than observed in control animals. While primary osteoblasts from Nrf2(-/-) mice functioned normally in vitro, the colony forming capacity of bone marrow stromal cells (BMSCs) from these mice was significantly reduced compared to controls. This defect could be rescued through treatment with the radical scavenger N-acetyl cysteine (NAC), suggesting that increased reactive species stress might impair early osteoblastogenesis in BMSCs and lead to the failure of bone acquisition observed in Nrf2(-/-) animals. Taken together, these studies suggest Nrf2 represents a key pathway in regulating bone metabolism, which may provide future therapeutic targets to treat osteoporosis.

No MeSH data available.


Related in: MedlinePlus

Nrf2 is required for normal postnatal bone acquisition. (a) Representative micro-CT images of trabecular bone structure in the distal femur of control and Nrf2βˆ’/βˆ’ mice at 8 weeks of age. (b–f) MicroCT analysis of trabecular bone structure at the distal femur in control and Nrf2βˆ’/βˆ’ mice at 3, 6, 8, 12 and 24 weeks of age (n=4–6 mice/group/age). Bone volume/tissue volume, BV/TV (%); bone area/tissue area, BA/TA (%); trabecular number, Tb. N (no./mm); trabecular thickness, Tb. Th (mm); Trabecular seperation, Tb. Sp (mm). Values shown are meanΒ±s.e.m.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4472135&req=5

fig1: Nrf2 is required for normal postnatal bone acquisition. (a) Representative micro-CT images of trabecular bone structure in the distal femur of control and Nrf2βˆ’/βˆ’ mice at 8 weeks of age. (b–f) MicroCT analysis of trabecular bone structure at the distal femur in control and Nrf2βˆ’/βˆ’ mice at 3, 6, 8, 12 and 24 weeks of age (n=4–6 mice/group/age). Bone volume/tissue volume, BV/TV (%); bone area/tissue area, BA/TA (%); trabecular number, Tb. N (no./mm); trabecular thickness, Tb. Th (mm); Trabecular seperation, Tb. Sp (mm). Values shown are meanΒ±s.e.m.

Mentions: Nrf2βˆ’/βˆ’ mice breed normally and have previously been reported to demonstrate normal growth patterns as compared to age-matched Nrf2+/+ mice. However, after 1 year of age, Nrf2βˆ’/βˆ’ mice begin to acquire autoimmune diseases not seen in their wild-type counterparts.43 In the course of investigating these autoimmune changes, we noted a difference in the bone strength of Nrf2βˆ’/βˆ’ mice while harvesting long bones to perform marrow flushes. The long bones of Nrf2βˆ’/βˆ’ mice seemed to be more fragile than those of their wild-type counterparts. Thus, to investigate the possibility of Nrf2 playing a previously unappreciated role in bone maintenance, we analyzed the long bones of Nrf2+/+ and Nrf2βˆ’/βˆ’ mice at 3, 6, 8, 12 and 24 weeks of age by micro-CT. As expected for C57BL6 mice, Nrf2+/+ mice attained peak bone mass by 8 weeks of age. By contrast, Nrf2βˆ’/βˆ’ mice demonstrated severely reduced bone mass at 3 weeks of age, which persisted through 12 weeks of age (Figure 1). Micro-CT analysis of the distal femur revealed approximately 45%, 30% and 20% reductions in bone volume fraction (BV/TV) in Nrf2βˆ’/βˆ’ mice compared to controls at 3, 6 and 8 weeks of age, respectively (Figure 1a and 1b). Trabecular number and thickness were decreased in Nrf2βˆ’/βˆ’ mice compared to controls, while trabecular separation was increased (Figure 1d–1f). However, by 12 weeks, all parameters were similar between Nrf2+/+ and Nrf2βˆ’/βˆ’ mice (Figure 1). Taken together, the result suggests that loss of Nrf2 impairs early postnatal bone acquisition.


Nrf2 is required for normal postnatal bone acquisition in mice.

Kim JH, Singhal V, Biswal S, Thimmulappa RK, DiGirolamo DJ - Bone Res (2014)

Nrf2 is required for normal postnatal bone acquisition. (a) Representative micro-CT images of trabecular bone structure in the distal femur of control and Nrf2βˆ’/βˆ’ mice at 8 weeks of age. (b–f) MicroCT analysis of trabecular bone structure at the distal femur in control and Nrf2βˆ’/βˆ’ mice at 3, 6, 8, 12 and 24 weeks of age (n=4–6 mice/group/age). Bone volume/tissue volume, BV/TV (%); bone area/tissue area, BA/TA (%); trabecular number, Tb. N (no./mm); trabecular thickness, Tb. Th (mm); Trabecular seperation, Tb. Sp (mm). Values shown are meanΒ±s.e.m.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4472135&req=5

fig1: Nrf2 is required for normal postnatal bone acquisition. (a) Representative micro-CT images of trabecular bone structure in the distal femur of control and Nrf2βˆ’/βˆ’ mice at 8 weeks of age. (b–f) MicroCT analysis of trabecular bone structure at the distal femur in control and Nrf2βˆ’/βˆ’ mice at 3, 6, 8, 12 and 24 weeks of age (n=4–6 mice/group/age). Bone volume/tissue volume, BV/TV (%); bone area/tissue area, BA/TA (%); trabecular number, Tb. N (no./mm); trabecular thickness, Tb. Th (mm); Trabecular seperation, Tb. Sp (mm). Values shown are meanΒ±s.e.m.
Mentions: Nrf2βˆ’/βˆ’ mice breed normally and have previously been reported to demonstrate normal growth patterns as compared to age-matched Nrf2+/+ mice. However, after 1 year of age, Nrf2βˆ’/βˆ’ mice begin to acquire autoimmune diseases not seen in their wild-type counterparts.43 In the course of investigating these autoimmune changes, we noted a difference in the bone strength of Nrf2βˆ’/βˆ’ mice while harvesting long bones to perform marrow flushes. The long bones of Nrf2βˆ’/βˆ’ mice seemed to be more fragile than those of their wild-type counterparts. Thus, to investigate the possibility of Nrf2 playing a previously unappreciated role in bone maintenance, we analyzed the long bones of Nrf2+/+ and Nrf2βˆ’/βˆ’ mice at 3, 6, 8, 12 and 24 weeks of age by micro-CT. As expected for C57BL6 mice, Nrf2+/+ mice attained peak bone mass by 8 weeks of age. By contrast, Nrf2βˆ’/βˆ’ mice demonstrated severely reduced bone mass at 3 weeks of age, which persisted through 12 weeks of age (Figure 1). Micro-CT analysis of the distal femur revealed approximately 45%, 30% and 20% reductions in bone volume fraction (BV/TV) in Nrf2βˆ’/βˆ’ mice compared to controls at 3, 6 and 8 weeks of age, respectively (Figure 1a and 1b). Trabecular number and thickness were decreased in Nrf2βˆ’/βˆ’ mice compared to controls, while trabecular separation was increased (Figure 1d–1f). However, by 12 weeks, all parameters were similar between Nrf2+/+ and Nrf2βˆ’/βˆ’ mice (Figure 1). Taken together, the result suggests that loss of Nrf2 impairs early postnatal bone acquisition.

Bottom Line: A large body of literature suggests that bone metabolism is susceptible to the ill effects of reactive species that accumulate in the body and cause cellular dysfunction.Despite the breadth of knowledge of both the function of Nrf2 and the effects of reactive species in bone metabolism, the direct role of Nrf2 in skeletal biology has yet to be thoroughly examined.Taken together, these studies suggest Nrf2 represents a key pathway in regulating bone metabolism, which may provide future therapeutic targets to treat osteoporosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health , Baltimore, MD, USA.

ABSTRACT
A large body of literature suggests that bone metabolism is susceptible to the ill effects of reactive species that accumulate in the body and cause cellular dysfunction. One of the body's front lines in defense against such damage is the transcription factor, Nrf2. This transcription factor regulates a plethora of antioxidant and cellular defense pathways to protect cells from such damage. Despite the breadth of knowledge of both the function of Nrf2 and the effects of reactive species in bone metabolism, the direct role of Nrf2 in skeletal biology has yet to be thoroughly examined. Thus, in the current study, we have examined the role of Nrf2 in postnatal bone metabolism in mice. Mice lacking Nrf2 (Nrf2(-/-)) exhibited a marked deficit in postnatal bone acquisition, which was most severe at 3 weeks of age when osteoblast numbers were 12-fold less than observed in control animals. While primary osteoblasts from Nrf2(-/-) mice functioned normally in vitro, the colony forming capacity of bone marrow stromal cells (BMSCs) from these mice was significantly reduced compared to controls. This defect could be rescued through treatment with the radical scavenger N-acetyl cysteine (NAC), suggesting that increased reactive species stress might impair early osteoblastogenesis in BMSCs and lead to the failure of bone acquisition observed in Nrf2(-/-) animals. Taken together, these studies suggest Nrf2 represents a key pathway in regulating bone metabolism, which may provide future therapeutic targets to treat osteoporosis.

No MeSH data available.


Related in: MedlinePlus