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Rheumatoid arthritis (RA) is a chronic inflammatory disease that causes irreversible joint damage and significant disability. However, the fundamental mechanisms underlying how inflammation and joint destruction in RA develop and are sustained chronically remain largely unknown. Here, we show that signal transducer and activator of transcription 3 (STAT3) is the key mediator of both chronic inflammation and joint destruction in RA. We found that inflammatory cytokines highly expressed in RA patients, such as IL-1β, tumor necrosis factor alpha and IL-6, activated STAT3 either directly or indirectly and in turn induced expression of IL-6 family cytokines, further activating STAT3 in murine osteoblastic and fibroblastic cells. STAT3 activation also induced expression of receptor activator of nuclear factor kappa B ligand (RANKL), a cytokine essential for osteoclastogenesis, and STAT3 deficiency or pharmacological inhibition promoted significant reduction in expression of both IL-6 family cytokines and RANKL in vitro. STAT3 inhibition was also effective in treating an RA model, collagen-induced arthritis, in vivo through significant reduction in expression of IL-6 family cytokines and RANKL, inhibiting both inflammation and joint destruction. Leukemia inhibitory factor expression and STAT3 activation by IL-1β were mainly promoted by IL-6 but still induced in IL-6-deficient cells. Thus, our data provide new insight into RA pathogenesis and provide evidence that inflammatory cytokines trigger a cytokine amplification loop via IL-6-STAT3 that promotes sustained inflammation and joint destruction.

In women, estrogen deficiency after menopause frequently accelerates osteoclastic bone resorption, leading to osteoporosis, the most common skeletal disorder. However, mechanisms underlying osteoporosis resulting from estrogen deficiency remain largely unknown. Here we show that in bone-resorbing osteoclasts, estrogendependent destabilization of hypoxia-inducible factor 1 alpha (HIF1α), which is unstable in the presence of oxygen, plays a pivotal role in promoting bone loss in estrogen-deficient conditions. In vitro, HIF1α was destabilized by estrogen treatment even in hypoxic conditions, and estrogen loss in ovariectomized (Ovx) mice stabilized HIF1α in osteoclasts and promoted their activation and subsequent bone loss in vivo. Osteoclast-specific HIF1α inactivation antagonized bone loss in Ovx mice and osteoclast-specific estrogen receptor alpha deficient mice, both models of estrogen-deficient osteoporosis. Oral administration of a HIF1α inhibitor protected Ovx mice from osteoclast activation and bone loss. Thus, HIF1α represents a promising therapeutic target in osteoporosis.B one mass is tightly regulated by a delicate balance between osteoblastic bone formation and osteoclastic bone resorption. Estrogen loss in women after menopause frequently promotes activation of osteoclastic bone resorption, causing osteoporosis. Osteoporotic bone phenotypes are seen in ovariectomized female mice, and estrogen deficiency-induced bone loss in both mouse models and women is ameliorated by estrogen treatment (1, 2). However, estrogen administration reportedly increases risk of cardiovascular events and carcinogenesis of the mammary gland and uterus (3). Bioavailable estrogens including selective estrogen receptor modulators (SERMs) also protect bone from estrogen deficiency-induced osteoporosis (4), and estrogen and SERMs primarily act via estrogen receptors (ER), ERα and ERβ (5, 6). However, how SERMs act on bone remains largely unknown. Thus, understanding of osteoclast activation following estrogen loss is crucial for development of safe therapeutic reagents.Both the endosteal zone of bone marrow cavities and epiphyseal growth plates are hypoxic areas, and the hypoxia-inducible factor (HIF) signaling pathway governs chondrocyte and osteoblast function in these respective areas (7,8). The HIF1 transcription factor consists of an oxygen-regulated alpha subunit, HIF1α, and a constitutively expressed beta subunit, HIF1β. Under normoxia, HIF1α is posttranslationally modified by prolyl hydroxylases, which catalyze hydroxylation of proline residues in the presence of O 2 and Fe 2+ . Recognition of hydroxylated HIF1α by the von Hippel-Lindau tumor suppressor protein recruits an E3 ubiquitin ligase complex targeting HIF1α for proteasomal degradation. Conversely, under hypoxia, proline hydroxylation is inhibited by substrate (O 2 ) deprivation, allowing HIF1α accumulation and formation of an active transcriptional complex with HIF1β (9). Recently, regulation of HIF1α protein levels by factors other than O 2 , including reactive ...

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The development of cancer is due to the growth and proliferation of transformed normal cells. Recent evidence suggests that the nature of oncogenic stress and the state of the cell of origin critically affect both tumorigenic activity and tumor histological type. However, this mechanistic relationship in mesenchymal tumors is currently largely unexplored. To clarify these issues, we established a mouse osteosarcoma (OS) model through overexpression of c-MYC in bone marrow stromal cells (BMSCs) derived from Ink4a/Arf (À/À) mice. Single-cell cloning revealed that c-MYC-expressing BMSCs are composed of two distinctly different clones: highly tumorigenic cells, similar to bipotent-committed osteochondral progenitor cells, and low-tumorigenic tripotent cells, similar to mesenchymal stem cells (MSCs). It is noteworthy that both bipotent and tripotent cells were capable of generating histologically similar, lethal OS, suggesting that both committed progenitor cells and MSCs can become OS cells of origin. Shifting mesenchymal differentiation by depleting PPARc in tripotent MSC-like cells and overexpressing PPARc in bipotent cells affected cell proliferation and tumorigenic activity. Our findings indicate that differentiation potential has a key role in OS tumorigenic activity, and that the suppression of adipogenic ability is a critical factor for the development of OS.