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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.


LysM-Cre; p38αf/f mice showed a decrease in bone formation at 2.5 or 6 month of age.(A) Two and half-month-old LysM-Cre; p38αf/f mice showed a decrease in BFR, MAR, and the number of osteoblasts per bone surface compared to control mice. N = 8. (B) Six-month-old LysM-Cre; p38αf/f mice showed a decrease in BFR, MAR, and the number of osteoblasts per bone surface compared to control mice. N = 8. (C) Two and half-month-old LysM-Cre; p38αf/f mice showed a decrease in the number of bone marrow colony forming units compared to control mice. Upper panel: ALP staining. Bottom panel: quantitation data. N = 3. (D) Six-month-old LysM-Cre; p38αf/f mice showed a decrease in the number of bone marrow colony forming units compared to control mice. Upper panel: ALP staining. Bottom panel: quantitation data. N = 3. For all results in Fig. 6, P-values are based on Student’s t-test. *p < 0.05, **p < 0.01 when the value of mutant mice or cells was compared to that of control mice or cells.
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f6: LysM-Cre; p38αf/f mice showed a decrease in bone formation at 2.5 or 6 month of age.(A) Two and half-month-old LysM-Cre; p38αf/f mice showed a decrease in BFR, MAR, and the number of osteoblasts per bone surface compared to control mice. N = 8. (B) Six-month-old LysM-Cre; p38αf/f mice showed a decrease in BFR, MAR, and the number of osteoblasts per bone surface compared to control mice. N = 8. (C) Two and half-month-old LysM-Cre; p38αf/f mice showed a decrease in the number of bone marrow colony forming units compared to control mice. Upper panel: ALP staining. Bottom panel: quantitation data. N = 3. (D) Six-month-old LysM-Cre; p38αf/f mice showed a decrease in the number of bone marrow colony forming units compared to control mice. Upper panel: ALP staining. Bottom panel: quantitation data. N = 3. For all results in Fig. 6, P-values are based on Student’s t-test. *p < 0.05, **p < 0.01 when the value of mutant mice or cells was compared to that of control mice or cells.

Mentions: Histomorphometry analysis also revealed that in 2.5- or 6-month-old mutant mice, the bone formation rate, mineral apposition rate, and the number of osteoblasts were all decreased compared to age-matched control mice (Fig. 6A and B). Since LysM does not label MSCs or osteoblasts, these results suggest that p38α deficiency may indirectly affect osteoblast proliferation and differentiation, for instance, by affecting the expression and secretion of coupling factors. We also compared the number of bone marrow ALP positive CFUs in LysM-Cre; p38αf/f and normal control mice, which is an indication of the number of MSCs, and found that p38α ablation in monocytes and osteoclasts led to a significant decrease in the number of MSCs in 2.5 or 6-month-old mice (Fig. 6C and D). These results suggest that p38α may regulate osteoclast synthesis and secretion of growth factors to regulate MSC proliferation and/or differentiation.


p38 α MAPK regulates proliferation and differentiation of osteoclast progenitors and bone remodeling in an aging-dependent manner
LysM-Cre; p38αf/f mice showed a decrease in bone formation at 2.5 or 6 month of age.(A) Two and half-month-old LysM-Cre; p38αf/f mice showed a decrease in BFR, MAR, and the number of osteoblasts per bone surface compared to control mice. N = 8. (B) Six-month-old LysM-Cre; p38αf/f mice showed a decrease in BFR, MAR, and the number of osteoblasts per bone surface compared to control mice. N = 8. (C) Two and half-month-old LysM-Cre; p38αf/f mice showed a decrease in the number of bone marrow colony forming units compared to control mice. Upper panel: ALP staining. Bottom panel: quantitation data. N = 3. (D) Six-month-old LysM-Cre; p38αf/f mice showed a decrease in the number of bone marrow colony forming units compared to control mice. Upper panel: ALP staining. Bottom panel: quantitation data. N = 3. For all results in Fig. 6, P-values are based on Student’s t-test. *p < 0.05, **p < 0.01 when the value of mutant mice or cells was compared to that of control mice or cells.
© Copyright Policy - open-access
Related In: Results  -  Collection

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f6: LysM-Cre; p38αf/f mice showed a decrease in bone formation at 2.5 or 6 month of age.(A) Two and half-month-old LysM-Cre; p38αf/f mice showed a decrease in BFR, MAR, and the number of osteoblasts per bone surface compared to control mice. N = 8. (B) Six-month-old LysM-Cre; p38αf/f mice showed a decrease in BFR, MAR, and the number of osteoblasts per bone surface compared to control mice. N = 8. (C) Two and half-month-old LysM-Cre; p38αf/f mice showed a decrease in the number of bone marrow colony forming units compared to control mice. Upper panel: ALP staining. Bottom panel: quantitation data. N = 3. (D) Six-month-old LysM-Cre; p38αf/f mice showed a decrease in the number of bone marrow colony forming units compared to control mice. Upper panel: ALP staining. Bottom panel: quantitation data. N = 3. For all results in Fig. 6, P-values are based on Student’s t-test. *p < 0.05, **p < 0.01 when the value of mutant mice or cells was compared to that of control mice or cells.
Mentions: Histomorphometry analysis also revealed that in 2.5- or 6-month-old mutant mice, the bone formation rate, mineral apposition rate, and the number of osteoblasts were all decreased compared to age-matched control mice (Fig. 6A and B). Since LysM does not label MSCs or osteoblasts, these results suggest that p38α deficiency may indirectly affect osteoblast proliferation and differentiation, for instance, by affecting the expression and secretion of coupling factors. We also compared the number of bone marrow ALP positive CFUs in LysM-Cre; p38αf/f and normal control mice, which is an indication of the number of MSCs, and found that p38α ablation in monocytes and osteoclasts led to a significant decrease in the number of MSCs in 2.5 or 6-month-old mice (Fig. 6C and D). These results suggest that p38α may regulate osteoclast synthesis and secretion of growth factors to regulate MSC proliferation and/or differentiation.

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.