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p38 α MAPK regulates proliferation and differentiation of osteoclast progenitors and bone remodeling in an aging-dependent manner

View Article: PubMed Central - PubMed

ABSTRACT

Bone mass is determined by the balance between bone formation, carried out by mesenchymal stem cell-derived osteoblasts, and bone resorption, carried out by monocyte-derived osteoclasts. Here we investigated the potential roles of p38 MAPKs, which are activated by growth factors and cytokines including RANKL and BMPs, in osteoclastogenesis and bone resorption by ablating p38α MAPK in LysM+monocytes. p38α deficiency promoted monocyte proliferation but regulated monocyte osteoclastic differentiation in a cell-density dependent manner, with proliferating p38α−/− cultures showing increased differentiation. While young mutant mice showed minor increase in bone mass, 6-month-old mutant mice developed osteoporosis, associated with an increase in osteoclastogenesis and bone resorption and an increase in the pool of monocytes. Moreover, monocyte-specific p38α ablation resulted in a decrease in bone formation and the number of bone marrow mesenchymal stem/stromal cells, likely due to decreased expression of PDGF-AA and BMP2. The expression of PDGF-AA and BMP2 was positively regulated by the p38 MAPK-Creb axis in osteoclasts, with the promoters of PDGF-AA and BMP2 having Creb binding sites. These findings uncovered the molecular mechanisms by which p38α MAPK regulates osteoclastogenesis and coordinates osteoclastogenesis and osteoblastogenesis.

No MeSH data available.


Related in: MedlinePlus

LysM-Cre; p38αf/f mice showed an increase in the size of monocyte pool.(A) The number of the bone marrow Gr1lowCD11b+ monocytes was increased in 6 month-old LysM-Cre; p38αf/f mice compared to control mice. N = 3. (B) The number of the bone marrow Gr1lowCD11b+ monocytes was increased in 2.5 month-old LysM-Cre; p38αf/f mice compared to control mice, to a lesser extent than that of 6-month-oldmice. N = 3. (C) Western blot showed that p38 MAPK activation was enhanced in the bone marrow monocytes isolated from 6-month-old normal mice compared to that of 2.5-month-old mice. BM cells were flushed out of the bones and purified with the Percoll method at 4 oC, which were directly used for western blot analysis. Results from two pairs of mice were shown. For all results in Fig. 5, P-values are based on Student’s t-test. *p < 0.05, **p < 0.01 when the value of mutant mice was compared to that of control mice.
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f5: LysM-Cre; p38αf/f mice showed an increase in the size of monocyte pool.(A) The number of the bone marrow Gr1lowCD11b+ monocytes was increased in 6 month-old LysM-Cre; p38αf/f mice compared to control mice. N = 3. (B) The number of the bone marrow Gr1lowCD11b+ monocytes was increased in 2.5 month-old LysM-Cre; p38αf/f mice compared to control mice, to a lesser extent than that of 6-month-oldmice. N = 3. (C) Western blot showed that p38 MAPK activation was enhanced in the bone marrow monocytes isolated from 6-month-old normal mice compared to that of 2.5-month-old mice. BM cells were flushed out of the bones and purified with the Percoll method at 4 oC, which were directly used for western blot analysis. Results from two pairs of mice were shown. For all results in Fig. 5, P-values are based on Student’s t-test. *p < 0.05, **p < 0.01 when the value of mutant mice was compared to that of control mice.

Mentions: Since p38α deficiency promotes monocyte proliferation, we compared the numbers of bone marrow monocytes between LysM-Cre; p38αf/f and age-matched control mice. Bone marrow monocytes can be labeled by Gr1lowCD11b+ 43. Flow cytometry analysis revealed that the percentage of monocytes in bone marrow was increased in 6-month-old LysM-Cre; p38αf/f mice compared to the age-matched control mice (Fig. 5A). The percentage of bone marrow monocytes were also increased in 2.5-month-old LysM-Cre; p38αf/f mice, yet to a much lesser extent than 6 month-old mice (Fig. 5B).


p38 α MAPK regulates proliferation and differentiation of osteoclast progenitors and bone remodeling in an aging-dependent manner
LysM-Cre; p38αf/f mice showed an increase in the size of monocyte pool.(A) The number of the bone marrow Gr1lowCD11b+ monocytes was increased in 6 month-old LysM-Cre; p38αf/f mice compared to control mice. N = 3. (B) The number of the bone marrow Gr1lowCD11b+ monocytes was increased in 2.5 month-old LysM-Cre; p38αf/f mice compared to control mice, to a lesser extent than that of 6-month-oldmice. N = 3. (C) Western blot showed that p38 MAPK activation was enhanced in the bone marrow monocytes isolated from 6-month-old normal mice compared to that of 2.5-month-old mice. BM cells were flushed out of the bones and purified with the Percoll method at 4 oC, which were directly used for western blot analysis. Results from two pairs of mice were shown. For all results in Fig. 5, P-values are based on Student’s t-test. *p < 0.05, **p < 0.01 when the value of mutant mice was compared to that of control mice.
© Copyright Policy - open-access
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5382695&req=5

f5: LysM-Cre; p38αf/f mice showed an increase in the size of monocyte pool.(A) The number of the bone marrow Gr1lowCD11b+ monocytes was increased in 6 month-old LysM-Cre; p38αf/f mice compared to control mice. N = 3. (B) The number of the bone marrow Gr1lowCD11b+ monocytes was increased in 2.5 month-old LysM-Cre; p38αf/f mice compared to control mice, to a lesser extent than that of 6-month-oldmice. N = 3. (C) Western blot showed that p38 MAPK activation was enhanced in the bone marrow monocytes isolated from 6-month-old normal mice compared to that of 2.5-month-old mice. BM cells were flushed out of the bones and purified with the Percoll method at 4 oC, which were directly used for western blot analysis. Results from two pairs of mice were shown. For all results in Fig. 5, P-values are based on Student’s t-test. *p < 0.05, **p < 0.01 when the value of mutant mice was compared to that of control mice.
Mentions: Since p38α deficiency promotes monocyte proliferation, we compared the numbers of bone marrow monocytes between LysM-Cre; p38αf/f and age-matched control mice. Bone marrow monocytes can be labeled by Gr1lowCD11b+ 43. Flow cytometry analysis revealed that the percentage of monocytes in bone marrow was increased in 6-month-old LysM-Cre; p38αf/f mice compared to the age-matched control mice (Fig. 5A). The percentage of bone marrow monocytes were also increased in 2.5-month-old LysM-Cre; p38αf/f mice, yet to a much lesser extent than 6 month-old mice (Fig. 5B).

View Article: PubMed Central - PubMed

ABSTRACT

Bone mass is determined by the balance between bone formation, carried out by mesenchymal stem cell-derived osteoblasts, and bone resorption, carried out by monocyte-derived osteoclasts. Here we investigated the potential roles of p38 MAPKs, which are activated by growth factors and cytokines including RANKL and BMPs, in osteoclastogenesis and bone resorption by ablating p38&alpha; MAPK in LysM+monocytes. p38&alpha; deficiency promoted monocyte proliferation but regulated monocyte osteoclastic differentiation in a cell-density dependent manner, with proliferating p38&alpha;&minus;/&minus; cultures showing increased differentiation. While young mutant mice showed minor increase in bone mass, 6-month-old mutant mice developed osteoporosis, associated with an increase in osteoclastogenesis and bone resorption and an increase in the pool of monocytes. Moreover, monocyte-specific p38&alpha; ablation resulted in a decrease in bone formation and the number of bone marrow mesenchymal stem/stromal cells, likely due to decreased expression of PDGF-AA and BMP2. The expression of PDGF-AA and BMP2 was positively regulated by the p38 MAPK-Creb axis in osteoclasts, with the promoters of PDGF-AA and BMP2 having Creb binding sites. These findings uncovered the molecular mechanisms by which p38&alpha; MAPK regulates osteoclastogenesis and coordinates osteoclastogenesis and osteoblastogenesis.

No MeSH data available.


Related in: MedlinePlus