Effects of inflammation on bone: An update
University of California, Department of Medicine, San Francisco VA Medical Center, San Francisco, CA, USA Current opinion in rheumatology
(Impact Factor: 4.89).
07/2011; 23(4):389-95. DOI: 10.1097/BOR.0b013e3283474dbe
To present an updated summary of the relationship between inflammation and localized and generalized bone loss in the rheumatic diseases.
In addition to the well established role of inflammatory cytokines in promoting enhanced osteoclast function and bone loss, recent work has discovered the cytokine milieu may also inhibit osteoblast function and bone repair. The WNT and bone morphogenetic protein pathways provide molecular links between inflammation and altered bone homeostasis in chronic inflammatory states. These pathways and others have been the targets of emerging therapies for the management of inflammatory bone loss.
Inflammation and bone loss are linked through a number of molecular pathways. Both of these processes need to be addressed when designing an effective treatment strategy for the rheumatic diseases.
Available from: Chao-Tsung Yang
- "Of particular note is Wnt/β-catenin signaling, which is necessary and sufficient for caudal fin regeneration (Kawakami et al., 2006; Stoick-Cooper et al., 2007a,b). Given the crucial role of Wnt/β-catenin signaling in zebrafish fin regeneration, as well as evidence that this pathway regulates macrophage chemotaxis, recruitment and inflammatory diseases in several mammalian models (Newman and Hughes, 2012; Matzelle et al., 2012; Baker-LePain et al., 2011; Whyte et al., 2012), Wnt/β-catenin signaling is a candidate for linking inflammation and regeneration in zebrafish. However, it is still relatively unclear how this key pathway is activated and how Wnt/β-catenin signaling affects specific cells and stages of the regenerative process. "
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ABSTRACT: Neutrophils and macrophages, as key mediators of inflammation, have defined functionally important roles in mammalian tissue repair. Although recent evidence suggests that similar cells exist in zebrafish and also migrate to sites of injury in larvae, whether these cells are functionally important for wound healing or regeneration in adult zebrafish is unknown. To begin to address these questions, we first tracked neutrophils (lyzC(+), mpo(+)) and macrophages (mpeg1(+)) in adult zebrafish following amputation of the tail fin, and detailed a migratory timecourse that revealed conserved elements of the inflammatory cell response with mammals. Next, we used transgenic zebrafish in which we could selectively ablate macrophages, which allowed us to investigate whether macrophages were required for tail fin regeneration. We identified stage-dependent functional roles of macrophages in mediating fin tissue outgrowth and bony ray patterning, in part through modulating levels of blastema proliferation. Moreover, we also sought to detail molecular regulators of inflammation in adult zebrafish and identified Wnt/β-catenin as a signaling pathway that regulates the injury microenvironment, inflammatory cell migration and macrophage phenotype. These results provide a cellular and molecular link between components of the inflammation response and regeneration in adult zebrafish.
Available from: Linda Gilbert
- "Chronic inflammation is known to mediate bone loss in a variety of conditions including rheumatoid arthritis and aging    . The joint space in rheumatoid arthritis represents the more severe end of the inflammation spectrum where tumor necrosis factor-α (TNF-α) has been shown to promote an inflammatory response, increase expression of receptor activator of nuclear factor kappa-B ligand (RANKL) and osteoclastic resorption  . Indeed, therapeutic intervention with anti-TNF drugs retards disease progression   . "
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ABSTRACT: The inflammatory cytokine tumor necrosis factor-α (TNF-α) is known to cause bone resorption and inhibit bone formation in arthritis and aging but less is known about TNF effects in the young growing skeleton. While investigating the mechanism of bone loss in TNF transgenic mice, we identified an early TNF-sensitive period marked by suppression of osteoblasts and bone accrual as the sole mechanism of TNF action, without an effect on osteoclasts or bone resorption. TgTNF mice express low concentrations of hTNFα (≤5 pg/ml). Osteoblasts cultured from TgTNF mice express reduced levels of RUNX2, Osx, alkaline phosphatase, bone sialoprotein, and osteocalcin and have delayed formation of mineralized nodules. Early accrual of bone in TgTNF mice is suppressed until 6 weeks of age, after which the rate of bone accrual normalizes without catch up. Histomorphometry revealed that TgTNF mice fail to generate a transient surge in osteoblast number that is seen in wild type (WT) mice at 4 weeks. Osteoclasts, TRAP staining, erosive surfaces, serum CTx, and OPG/RANKL expression did not differ between young TgTNF and WT mice. Canonical Wnts and signaling through β-catenin were reduced in TgTNF mice at 4 weeks and partially recovered by 12 weeks, associated with reduced cytoplasm to nuclear transfer of β-catenin and Wnt regulated genes. TgTNF mice were crossed with BatGal Wnt reporter mice. Active Wnt signaling in tibial trabecular lining cells was reduced in TgTNF mice at 4 weeks compared to control littermates. Our results demonstrate that a low dose inflammatory stimulus is sufficient to inhibit the early surge in osteoblasts and optimal bone formation of young mice independent of changes in osteoclasts. TNF inhibition of the Wnt pathway contributes to the suppression of osteoblasts.
Available from: europepmc.org
- "The cytokine milieu determines the effects of inflammation on bone. There is extensive research on the role of proinflammatory cytokines in bone homeostasis (23–25). Blockade of the inflammatory cytokines results in the control of chronic inflammation as well as in protective effects on bone. "
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ABSTRACT: Bone destruction and inflammation are closely linked. Cytokines play an important role in inflammatory bone destruction by upregulating the receptor activator of nuclear factor-κB (NF-κB) ligand (RANKL). The direct role of cytokines that act in a non-RANKL-dependent manner has yet to be elucidated. The aim of this study was to investigate the direct osteoclastogenic properties of inflammatory cytokines at different time-points of osteoclastogenesis. Mouse bone marrow macrophages were stimulated with the macrophage colony-stimulating factor (M-CSF) and various concentrations of RANKL. Inflammatory cytokines, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, IL-17 and IL-23, were added to the culture system of osteoclastogenesis. Two time-points of cytokine treatment were set. The 'early' effect of each cytokine was investigated at the time of first RANKL treatment, whereas the 'late' effect was investigated 48 h after the first RANKL challenge. Osteoclast differentiation and function were assessed using an osteoclast marker [tartrate-resistant acid phosphatase (TRAP)] and by visualization of pit formation. A permissive level of RANKL was required for cytokine-associated osteoclastogenesis in all experiments. In the M-CSF/RANKL monocellular culture system, IL-1β enhanced and IL-6 decreased osteoclast formation in a dose-dependent manner, regardless of temporal differences. Other cytokines showed various responses according to the phase of osteoclast maturation and the concentration of each cytokine and RANKL. Furthermore, luciferase assays showed that both IL-1β and RANKL activated the NF-κB signaling pathway. Collectively, our data revealed that targeting IL-1β may be a promising strategy to inhibit inflammation-associated bone destruction and osteoporosis.
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