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Ablation of p38α MAPK Signaling in Osteoblast Lineage Cells Protects Mice From Bone Loss Induced by Estrogen
Cyril Thouverey1, Joseph Caverzasio1
1Service of Bone Diseases, Department of Internal Medicine Specialties, University Hospital of Geneva, 1205 Geneva, Switzerland.
Abstract:
Estrogen deficiency causes bone loss by increasing the number of bone-resorbing osteoclasts. Selective p38α MAPK inhibitors prevent bone-wasting effects of estrogen withdrawal but implicated mechanisms remain to be identified. Here, we show that inactivation of the p38α-encoding gene in osteoblast lineage cells with the use of an osteocalcin-cre transgene protects mice from ovariectomy-induced bone loss (a murine model of postmenopausal osteoporosis). Ovariectomy fails to induce bone loss, increase bone resorption, and stimulate receptor activator of nuclear factor κB ligand and IL-6 expression in mice lacking p38α in osteoblasts and osteocytes. Finally, TNFα or IL-1, which are osteoclastogenic cytokines overproduced in the bone marrow under estrogen deficiency, can activate p38α signaling in osteoblasts, but those cytokines cannot enhance Rankl and Il6 expressions or increase osteoclast formation in p38a-deficient osteoblast cultures. These findings demonstrate that p38α MAPK signaling in osteoblast lineage cells mediates ovariectomy-induced bone loss by up-regulating receptor activator of nuclear factor κB ligand and IL-6 production.
Insights
Selective p38α MAPK inhibitors prevent bone loss from estrogen deficiency. Inactivating p38α in osteoblasts protects against osteoporosis by reducing bone resorption and key inflammatory signals.
Area of Science:
- Bone Biology
- Endocrinology
- Molecular Signaling
Background:
- Estrogen deficiency accelerates bone loss by increasing osteoclast activity.
- p38α MAPK inhibitors show promise in preventing bone loss, but the precise mechanisms are unclear.
Purpose of the Study:
- To investigate the role of p38α MAPK signaling in osteoblast lineage cells in postmenopausal osteoporosis.
- To elucidate the molecular mechanisms by which p38α MAPK contributes to estrogen deficiency-induced bone loss.
Main Methods:
- Utilized an osteocalcin-cre transgene to specifically inactivate the p38α-encoding gene in osteoblast lineage cells in mice.
- Assessed bone loss, bone resorption, and expression of key cytokines (RANKL, IL-6) following ovariectomy.
- Examined the effect of TNFα and IL-1 on p38α signaling and osteoclastogenesis in p38α-deficient osteoblast cultures.
Main Results:
- Mice lacking p38α in osteoblasts and osteocytes were protected from ovariectomy-induced bone loss.
- Ovariectomy failed to increase bone resorption or stimulate RANKL and IL-6 expression in these mice.
- TNFα and IL-1 could not enhance RANKL and IL-6 expression or osteoclast formation in p38α-deficient osteoblast cultures.
Conclusions:
- p38α MAPK signaling within the osteoblast lineage is crucial for mediating bone loss associated with estrogen deficiency.
- This signaling pathway up-regulates receptor activator of nuclear factor κB ligand (RANKL) and IL-6, thereby promoting osteoclast activity and bone resorption.
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