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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.

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LysM-Cre; p38αf/f mice showed distinct alterations in bone resorption at 2.5 and 6 month of age.(A) Two and half-month-old LysM-Cre; p38αf/f mice showed a slight decrease in erosion surface, osteoclast surface, osteoclast number, and urine DPD levels compared to control mice. N = 8. (B) Six-month-old LysM-Cre; p38αf/f mice showed an increase in erosion surface, osteoclast surface, osteoclast number, and urine DPD levels compared to control mice. N = 8. (C) In vivo TRAP staining showed that the femur bones of 2.5-month-old LysM-Cre; p38αf/f mice exhibited a minor decrease in osteoclasts compared to control mice. Scale bar, 200 μm. N = 3. (D) In vivo TRAP staining showed that the femur bones of 6-month-old LysM-Cre; p38αf/f mice exhibited an increase in osteoclasts compared to control mice. Scale bar, 50 μm. N = 3. For all results in Fig. 4, P-values are based on Student’s t-test. **p < 0.01 when the value of mutant mice or cells was compared to that of control mice.
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f4: LysM-Cre; p38αf/f mice showed distinct alterations in bone resorption at 2.5 and 6 month of age.(A) Two and half-month-old LysM-Cre; p38αf/f mice showed a slight decrease in erosion surface, osteoclast surface, osteoclast number, and urine DPD levels compared to control mice. N = 8. (B) Six-month-old LysM-Cre; p38αf/f mice showed an increase in erosion surface, osteoclast surface, osteoclast number, and urine DPD levels compared to control mice. N = 8. (C) In vivo TRAP staining showed that the femur bones of 2.5-month-old LysM-Cre; p38αf/f mice exhibited a minor decrease in osteoclasts compared to control mice. Scale bar, 200 μm. N = 3. (D) In vivo TRAP staining showed that the femur bones of 6-month-old LysM-Cre; p38αf/f mice exhibited an increase in osteoclasts compared to control mice. Scale bar, 50 μm. N = 3. For all results in Fig. 4, P-values are based on Student’s t-test. **p < 0.01 when the value of mutant mice or cells was compared to that of control mice.

Mentions: Histomorphometry analysis showed that the modest increase in bone mass in 2.5-month-old mice was associated with a decrease in bone resorption (Fig. 4A). The bone erosion surfaces and the number of osteoclasts per bone surface were decreased (Fig. 4A). In addition, the levels of urine DPD, an in vivo marker of bone resorption, was also decreased (Fig. 4A). The decrease in the number of osteoclasts could only be explained by compromised differentiation of osteoclasts, as p38α deficiency promoted monocyte proliferation.


p38 α MAPK regulates proliferation and differentiation of osteoclast progenitors and bone remodeling in an aging-dependent manner
LysM-Cre; p38αf/f mice showed distinct alterations in bone resorption at 2.5 and 6 month of age.(A) Two and half-month-old LysM-Cre; p38αf/f mice showed a slight decrease in erosion surface, osteoclast surface, osteoclast number, and urine DPD levels compared to control mice. N = 8. (B) Six-month-old LysM-Cre; p38αf/f mice showed an increase in erosion surface, osteoclast surface, osteoclast number, and urine DPD levels compared to control mice. N = 8. (C) In vivo TRAP staining showed that the femur bones of 2.5-month-old LysM-Cre; p38αf/f mice exhibited a minor decrease in osteoclasts compared to control mice. Scale bar, 200 μm. N = 3. (D) In vivo TRAP staining showed that the femur bones of 6-month-old LysM-Cre; p38αf/f mice exhibited an increase in osteoclasts compared to control mice. Scale bar, 50 μm. N = 3. For all results in Fig. 4, P-values are based on Student’s t-test. **p < 0.01 when the value of mutant mice or cells was compared to that of control mice.
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Related In: Results  -  Collection

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f4: LysM-Cre; p38αf/f mice showed distinct alterations in bone resorption at 2.5 and 6 month of age.(A) Two and half-month-old LysM-Cre; p38αf/f mice showed a slight decrease in erosion surface, osteoclast surface, osteoclast number, and urine DPD levels compared to control mice. N = 8. (B) Six-month-old LysM-Cre; p38αf/f mice showed an increase in erosion surface, osteoclast surface, osteoclast number, and urine DPD levels compared to control mice. N = 8. (C) In vivo TRAP staining showed that the femur bones of 2.5-month-old LysM-Cre; p38αf/f mice exhibited a minor decrease in osteoclasts compared to control mice. Scale bar, 200 μm. N = 3. (D) In vivo TRAP staining showed that the femur bones of 6-month-old LysM-Cre; p38αf/f mice exhibited an increase in osteoclasts compared to control mice. Scale bar, 50 μm. N = 3. For all results in Fig. 4, P-values are based on Student’s t-test. **p < 0.01 when the value of mutant mice or cells was compared to that of control mice.
Mentions: Histomorphometry analysis showed that the modest increase in bone mass in 2.5-month-old mice was associated with a decrease in bone resorption (Fig. 4A). The bone erosion surfaces and the number of osteoclasts per bone surface were decreased (Fig. 4A). In addition, the levels of urine DPD, an in vivo marker of bone resorption, was also decreased (Fig. 4A). The decrease in the number of osteoclasts could only be explained by compromised differentiation of osteoclasts, as p38α deficiency promoted monocyte proliferation.

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