Cytokine-induced inhibition of bone matrix proteins is not mediated by prostaglandins (original) (raw)
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Role of prostaglandins in interleukin-1-induced bone resorption in mice in vitro
Journal of Bone and Mineral Research, 2009
The mechanism of bone resorption induced by interleukin 1 (IL-1) was examined in mice using three different in vitro assay systems: a fetal long bone organ culture system, a bone marrow culture system, and a coculture system of primary osteoblastic cell populations and spleen cells. In the organ culture system, recombinant human IL-la (rhIL-la) increased both bone resorption and osteoclast number. Both were partially suppressed in the presence of indomethacin. In the marrow culture, both rhIL-la and rhIL-10 stimulated osteoclastlike cell formation, which was completely inhibited by adding indomethacin concurrently. Furthermore, there was a good correlation between the number of osteoclastlike cells formed and the amount of prostaglandin E, (PGE,) released into the culture media. This indicates that PGE, is involved in the mechanism of IL-1-mediated osteoclastlike cell formation. In the coculture of primary osteoblastic cell populations and spleen cells, rhIL-1 again stimulated osteoclastlike cell formation, which was inhibited by adding indomethacin. In the cocultures in which direct interaction between osteoblastic cells and spleen cells was inhibited, PGE, synthesis was similarly increased but no osteoclastlike cells were formed. These results indicate that IL-1 induces osteoclast formation by a mechanism involving PG (most likely PGE,). Furthermore, direct interaction between osteoclast progenitors and osteoblastic cells is required in the osteoclast recruitment induced by IL-1.
Journal of Bone and Mineral Research, 2009
Human recombinant tumor necrosis factors a and 0 (TNF-a and TNF-P), at and above 1 ng/ml (P 70 pM), caused a dose-and time-dependent enhancement of 45Ca release from neonatal mouse calvarial bones in vitro. In addition, TNF-a and TNF-/3 (3-100 ng/ml) caused a dose-dependent stimulation of prostaglandin E, (PGE,) formation in the calvarial bones. TNF-(r also enhanced the biosynthesis of PGI,, as assessed by analysis of the stable breakdown product 6-keto-PGF1,. The stimulatory actions of TNF-cu and TNF-@ on PGE, formation was maximal at 12 h. Indomethacin, flurbiprofen, and meclofenamic acid, three structurally unrelated nonsteroidal antiinflammatory drugs, abolished PGE, biosynthesis induced by TNF-a! and TNF-P (100 ng/ml). The 45Ca release stimulated by TNF-a and TNF-P (100 ng/ml), however, was only slightly reduced by indomethacin, flurbiprofen, and meclofenamic acid. The partial inhibitory effect of indomethacin on 45Ca release was seen over a wide range of TNF-a concentrations, without affecting the concentration producing half-maximal stimulatory response. TNF-a and TNF-0 (100 ng/ml) stimulated bone matrix breakdown, as assessed by analysis of the release of 3H from bone prelabeled with ['Hlproline. Also, the stimulatory effect of TNF-a and TNF-6 on bone matrix degradation was partially reduced by indomethacin. Hydrocortisone (1 pM) and dexamethasone (0.1 pM) abolished TNF-a-and TNF-0-induced production of PGE,. In contrast to the cyclooxygenase inhibitors, the corticosteroids did not affect the stimulatory action by the cytokines on 45Ca release. These observations suggest that TNF-a and TNF-0 can stimulate bone resorption in vitro by prostaglandin-independent mechanisms.
Lights and shadows of NSAIDs in bone healing: the role of prostaglandins in bone metabolism
Drug Design Development and Therapy, 2018
In this review, we discuss the current data about the anatomy and function of bone tissue with particular regard to influence of prostaglandins. Bone tissue dynamics are characterized by a constant remodeling process that involves all bone tissue cells. The communication between bone component cells and other organs is necessary for bone remodeling equilibrium and confirms the dynamic character of bone tissue. Remodeling is also a vital element of healing processes and in adapting bone tissue to stress responses. Therefore, in our review we present the role and significance of bone cells and signaling pathways enabling maintenance of bone homeostasis and remodeling process stability. Cyclooxygenase (COX) is a crucial enzyme in the production of prostaglandins and thromboxane. We focus on the role of COX isoenzymes with highlighting their connection with bone formation, resorption and repair. Prostaglandins are known as arachidonic acid metabolites acting through specific membrane receptors and play an important role in the regulation of osteoblast and osteoclast functions. Prostaglandin PGE2 with its four defined receptors (EP1R, EP2R, EP3R and EP4R) is crucial to maintain balanced bone turnover. Their stimulatory or inhibitory effects appear to depend on different structure-activity relations and signaling pathways. We have described the role of these receptors in bone metabolism and healing. We conclude that the activity of prostaglandins in bone tissue is defined by maintaining bone remodeling balance and its reactions to humoral mediators and mechanical stress. Most data confirm that among prostaglandins, PGE2 takes part in all processes of trauma response, including homeostasis, inflammation and healing, and plays a key role in bone physiology.
Proinflammatory cytokine expression in cyclooxygenase-2-deficient primary osteoblasts
Journal of Endodontics, 2007
Many of the proinflammatory effects of interleukin (IL)-1 and tumor necrosis factor-␣ (TNF-␣) are mediated through cyclooxygenase-2 (COX-2)-dependent prostaglandin E2 (PGE2). The purpose of this study was to examine the expression of IL-1 and TNF-␣ in COX-2-deficient osteoblasts during inflammation. Primary osteoblasts prepared from wild-type (WT) and COX-2 knockout (K/O) mice were exposed to lipopolysaccharide (LPS) and endodontic obturation materials. An enzyme-linked immunosorbent assay was used to measure cytokine levels. LPS treatment led to a significant upregulation in IL-1 and TNF-␣ levels in both WT and K/O cells. TNF-␣ upregulation in response to LPS was much more pronounced in K/O cells compared with WT cells (p Ͻ 0.05). All materials tested except for gutta percha caused an increase in IL-1 expression. In conclusion, there appears to be a positive feedback regulation between TNF-␣ and COX-2-dependent PGE2 during LPSinduced inflammatory reactions.
Prostaglandin E 2 Strongly Inhibits Human Osteoclast Formation
Endocrinology, 2005
Prostaglandin E 2 (PGE 2 ) enhances osteoclast formation in mouse macrophage cultures treated with receptor activator of nuclear factor-B ligand (RANKL). The effects of PGE 2 on human osteoclast formation were examined in cultures of CD14 ؉ cells prepared from human peripheral blood mononuclear cells. CD14 ؉ cells differentiated into osteoclasts in the presence of RANKL and macrophage colony-stimulating factor. CD14 ؉ cells expressed EP2 and EP4, but not EP1 or EP3, whereas CD14 ؉ cell-derived osteoclasts expressed none of the PGE 2 receptors. PGE 2 and PGE 1 alcohol (an EP2/4 agonist) stimulated cAMP production in CD14 ؉ cells. In contrast to mouse macrophage cultures, PGE 2 and PGE 1 alcohol inhibited RANKL-induced human osteoclast formation in CD14 ؉ cell cultures. H-89 blocked the inhibitory effect of PGE 2 on human osteoclast formation. These results suggest that the
Osteoimmunology and the influence of pro-inflammatory cytokines on osteoclasts
Biochemia Medica, 2013
Bone and immune system are functionally interconnected. Immune and bone cells derive from same progenitors in the bone marrow, they share a common microenvironment and are being infl uenced by similar mediators. The evidence on increased bone resorption associated with inappropriate activation of T cells such as during infl ammation, is well established. However, the molecular mechanisms beyond this clinical observation have begun to be intensively studied with the advancement of osteoimmunology. Now days, we have fi rm evidence on the infl uence of numerous proinfl ammatory cytokines on bone cells, with the majority of data focused on osteoclasts, the bone resorbing cells. It has been shown that some proinfl ammatory cytokines could possess osteoclastogenic and/or anti-osteoclastogenic properties and can target osteoclasts directly or via receptor activator of nuclear factor κB (RANK)/RANK ligand(RANKL)/osteoprotegerin (OPG) system. Several studies have reported opposing data regarding (anti)osteoclastogenic properties of these cytokines. Therefore, the fi rst part of this review is summarizing current evidence on the infl uence of pro-infl ammatory cytokines on osteoclasts and thus on bone resorption. In the second part, the evidence on the role of pro-infl ammatory cytokines in osteoporosis and osteoarthritis is reviewed to show that unravelling the mechanisms beyond such complex bone diseases, is almost impossible without considering skeletal and immune systems as an indivisible integrated system.
Inhibitory and stimulatory effects of prostaglandins on osteoclast differentiation
Calcified Tissue International, 1997
The effect of prostaglandins (PGs) on osteoclast differentiation, an important point of control for bone resorption, is poorly understood. After an initial differentiation phase that lasts at least 4 days, murine monocytes, cocultured with UMR 1 06 osteoblastic cells (in the presence of 1,25-dihydroxyvitamin D 3 ) give rise to tartrate-resistant acid phosphatase (TRAP) positive osteoclast-like cells that are capable of lacunar bone resorption. PGE 2 strongly inhibits TRAP expression and bone resorption in these cocultures. To examine further the cellular mechanisms associated with this inhibitory effect, we added PGE 2 to monocyte/UMR 106 cocultures at specific times before, during, and after this initial 4-day differentiation period. To determine whether this PGE 2 inhibition was dependent on the type of stromal cell supporting osteoclast differentiation, we also added PGE 2 to cocultures of monocytes with ST2 preadipocytic cells.
Bone-resorbing activity and prostaglandin E produced by human periodontal ligament cells in vitro
Journal of Bone and Mineral Research, 2009
Human periodontal ligament (PDL) cells were derived from healthy premolars extracted for orthodontic treatment and were utilized for in vitro experiments in passages 4-6. Human PDL cells were seeded in tissue culture tubes and incubated with interleukin-la (IL-la), IL-10, tumor necrosis factor-a (TNF-a), interferon-y (IFN-y), indomethacin, parathyroid hormone (PTH), or their combinations, for 1 h. The medium was then replaced with serum-free BGJb medium and incubated for 24 h without further additions. Prostaglandin E (PGE) concentrations in the conditioned media (CM) were measured by radioimmunoassay, and bone-resorbing activity was measured using 45Ca-labeled neonatal mouse calvariae. The results of this study indicated that (1) unstimulated cultured PDL cells produced PGE, and PDL CM stimulated bone resorption;
Journal of Endocrinology, 2001
Prostaglandin E(2) (PGE(2)) has been shown to exert a bone anabolic effect in young and adult rats. In this study we tested whether it possesses a similar effect on bone formation and bone mass in aging rats. Fifteen-month-old rats were injected daily with either PGE(2) at 5 mg/kg or vehicle for 14 days. PGE(2) treatment stimulated the rate of cancellous bone formation (a approximately 5.5-fold increase in bone formation rate), measured by the incorporation of calcein into bone-forming surfaces at the tibial proximal metaphysis. This effect resulted in increased cancellous bone area (+54%) at the same site. Since PGE(2) treatment resulted in a much higher proportion of bone surface undergoing bone formation and thus lined with osteoblasts, we tested the hypothesis that PGE(2) stimulates osteoblast differentiation from bone marrow precursor cells both in vivo and in vitro. We found that ex vivo cultures of bone marrow stromal cells from rats injected for 2 weeks with PGE(2) at 5 mg/k...
IMPACT OF CYTOKINES ON BONE HOMEOSTASIS
Cytokines are involved in the regulation of the immune system and clearly communicate with immune cells and bone cells. Therefore, cytokines are produced by many different cell types and are state. Cytokines such as IL-1, TNF, IL-6, TGF-b, IL-2, IL-8, M-CSF, IL-12, IL-18 and IFN-, and anti-resorption. The immune system and bone cells require positive and negative regulators to maintain homeostasis. In this article, we discuss the interactions between cytokines and bone cells in maintaining homeostasis of the bone. However, the relationship between intercellular signalling, osteoprogenitor cells, mature osteoblasts, osteocytes and osteoclasts, in regulating the pathophysiology of the bone, still remains to be elucidated. Editorial.