Estrogen prevents osteoporotic bone loss by attenuating bone resorption; however, the molecular basis for this is unknown. Here, we report a critical role for the osteoclastic estrogen receptor alpha (ERalpha) in mediating estrogen-dependent bone maintenance in female mice. We selectively ablated ERalpha in differentiated osteoclasts (ERalpha(DeltaOc/DeltaOc)) and found that ERalpha(DeltaOc/DeltaOc) females, but not males, exhibited trabecular bone loss, similar to the osteoporotic bone phenotype in postmenopausal women. Further, we show that estrogen induced apoptosis and upregulation of Fas ligand (FasL) expression in osteoclasts of the trabecular bones of WT but not ERalpha(DeltaOc/DeltaOc) mice. The expression of ERalpha was also required for the induction of apoptosis by tamoxifen and estrogen in cultured osteoclasts. Our results support a model in which estrogen regulates the life span of mature osteoclasts via the induction of the Fas/FasL system, thereby providing an explanation for the osteoprotective function of estrogen as well as SERMs.

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Based on the fact that aging is associated with a reciprocal decrease of osteogenesis and an increase of adipogenesis in bone marrow and that osteoblasts and adipocytes share a common progenitor, this study investigated the role of PPARγ γ, a key regulator of adipocyte differentiation, in bone metabolism. Homozygous PPARγ γ-deficient ES cells failed to differentiate into adipocytes, but spontaneously differentiated into osteoblasts, and these were restored by reintroduction of the PPARγ γ gene. Heterozygous PPARγ γ-deficient mice exhibited high bone mass with increased osteoblastogenesis, but normal osteoblast and osteoclast functions, and this effect was not mediated by insulin or leptin. The osteogenic effect of PPARγ γ haploinsufficiency became prominent with aging but was not changed upon ovariectomy. The PPARγ γ haploinsufficiency was confirmed to enhance osteoblastogenesis in the bone marrow cell culture but did not affect the cultures of differentiated osteoblasts or osteoclast-lineage cells. This study demonstrates a PPARγ γ-dependent regulation of bone metabolism in vivo, in that PPARγ γ insufficiency increases bone mass by stimulating osteoblastogenesis from bone marrow progenitors.Nonstandard abbreviations used: alkaline phosphatase (ALP); bone morphogenetic protein-2 (BMP-2); bone volume (BV); CCAAT enhancer-binding proteins (C/EBPs); computed tomography (CT); LDL receptor-related protein 5 (LRP5); leukemia inhibitory factor (LIF); M-CSF-dependent bone marrow macrophage (M-BMMφ); receptor activator of nuclear factor κB ligand (RANKL); ovariectomy (OVX); PPAR responsive element (PPRE); tartrate-resistant acid phosphatase (TRAP); tissue volume (TV); type I collagen α1 chain (COL1A1).

Based on the fact that aging is associated with a reciprocal decrease of osteogenesis and an increase of adipogenesis in bone marrow and that osteoblasts and adipocytes share a common progenitor, this study investigated the role of PPARγ γ, a key regulator of adipocyte differentiation, in bone metabolism. Homozygous PPARγ γ-deficient ES cells failed to differentiate into adipocytes, but spontaneously differentiated into osteoblasts, and these were restored by reintroduction of the PPARγ γ gene. Heterozygous PPARγ γ-deficient mice exhibited high bone mass with increased osteoblastogenesis, but normal osteoblast and osteoclast functions, and this effect was not mediated by insulin or leptin. The osteogenic effect of PPARγ γ haploinsufficiency became prominent with aging but was not changed upon ovariectomy. The PPARγ γ haploinsufficiency was confirmed to enhance osteoblastogenesis in the bone marrow cell culture but did not affect the cultures of differentiated osteoblasts or osteoclast-lineage cells. This study demonstrates a PPARγ γ-dependent regulation of bone metabolism in vivo, in that PPARγ γ insufficiency increases bone mass by stimulating osteoblastogenesis from bone marrow progenitors.Nonstandard abbreviations used: alkaline phosphatase (ALP); bone morphogenetic protein-2 (BMP-2); bone volume (BV); CCAAT enhancer-binding proteins (C/EBPs); computed tomography (CT); LDL receptor-related protein 5 (LRP5); leukemia inhibitory factor (LIF); M-CSF-dependent bone marrow macrophage (M-BMMφ); receptor activator of nuclear factor κB ligand (RANKL); ovariectomy (OVX); PPAR responsive element (PPRE); tartrate-resistant acid phosphatase (TRAP); tissue volume (TV); type I collagen α1 chain (COL1A1).

We examined the in vivo role of membrane-bound prostaglandin E synthase (mPGES)-1, a terminal enzyme in the PGE 2 -biosynthetic pathway, using mPGES-1 knockout (KO) mice. Comparison of PGES activity in the membrane fraction of tissues from mPGES-1 KO and wild-type (WT) mice indicated that mPGES-1 accounted for the majority of lipopolysaccharide (LPS)-inducible PGES in WT mice. LPS-stimulated production of PGE 2 , but not other PGs, was impaired markedly in mPGES-1-null macrophages, although a low level of cyclooxygenase-2-dependent PGE 2 production still remained. Pain nociception, as assessed by the acetic acid writhing response, was reduced significantly in KO mice relative to WT mice. This phenotype was particularly evident when these mice were primed with LPS, where the stretching behavior and the peritoneal PGE 2 level of KO mice were far less than those of WT mice. Formation of inflammatory granulation tissue and attendant angiogenesis in the dorsum induced by subcutaneous implantation of a cotton thread were reduced significantly in KO mice compared with WT mice. Moreover, collagen antibody-induced arthritis, a model for human rheumatoid arthritis, was milder in KO mice than in WT mice. Collectively, our present results provide unequivocal evidence that mPGES-1 contributes to the formation of PGE 2 involved in pain hypersensitivity and inflammation.