SP500263, a novel SERM, blocks osteoclastogenesis in a human bone cell model: role of IL-6 and GM-CSF

Sutherland, May Kung; Lipps, Stephanie; Patnaik, Nandita; Gayo‐Fung, Leah M.; Khammungkune, Sak; Xie, Weilin; Brady, Helen; Barbosa, Miguel; Anderson, David W.; Stein, Bernd

doi:10.1016/s1043-4666(03)00179-0

Cited by 21 publications

(13 citation statements)

References 62 publications

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“…Previous osteoclast assays for measurement of compound activity were either done with non-human cells (mouse, rat, rabbit) [12-14], or, if they used human cells, were done with a human monocytic cell line in co-cultures with osteoblastic cells [15], or used human bone marrow-derived osteoclasts [4], or human tumor osteoclastoma-derived cells [9]. Although useful, these methods do not use active primary human osteoclasts.…”

Section: Discussionmentioning

confidence: 99%

Human primary osteoclasts: in vitro generation and applications as pharmacological and clinical assay

et al. 2004

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Osteoclasts are cells of hematopoietic origin with a unique property of dissolving bone; their inhibition is a principle for treatment of diseases of bone loss. Protocols for generation of human osteoclasts in vitro have been described, but they often result in cells of low activity, raising questions on cell phenotype and suitability of such assays for screening of bone resorption inhibitors. Here we describe an optimized protocol for the production of stable amounts of highly active human osteoclasts. Mononuclear cells were isolated from human peripheral blood by density centrifugation, seeded at 600,000 cells per 96-well and cultured for 17 days in α-MEM medium, supplemented with 10% of selected fetal calf serum, 1 μM dexamethasone and a mix of macrophage-colony stimulating factor (M-CSF, 25 ng/ml), receptor activator of NFκB ligand (RANKL, 50 ng/ml), and transforming growth factor-β1 (TGF-β1, 5 ng/ml). Thus, in addition to widely recognized osteoclast-generating factors M-CSF and RANKL, other medium supplements and lengthy culture times were necessary. This assay reliably detected inhibition of osteoclast formation (multinucleated cells positive for tartrate-resistant acid phosphatase) and activity (resorbed area and collagen fragments released from bone slices) in dose response curves with several classes of bone resorption inhibitors. Therefore, this assay can be applied for monitoring bone-resorbing activity of novel drugs and as an clinical test for determining the capacity of blood cells to generate bone-resorbing osteoclasts. Isolation of large quantities of active human osteoclast mRNA and protein is also made possible by this assay.

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Section: Discussionmentioning

confidence: 99%

Human primary osteoclasts: in vitro generation and applications as pharmacological and clinical assay

et al. 2004

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“…Neutralising antibodies to IL-6 decrease the formation of osteoclast-like cells 37. Furthermore, increased circulating IL-6 levels in paediatric IBD patients are negatively correlated with BMD38 and IL-6 gene polymorphisms influence BMD in patients with Crohn’s disease (fig 1B).…”

Section: Inflammation and Bone Loss: Cell Types And Mediators Involvementioning

confidence: 98%

Gut, inflammation and osteoporosis: basic and clinical concepts

Tilg

Moschen

Kaser

et al. 2008

Gut

247

167

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Chronic inflammatory disorders such as inflammatory bowel diseases (IBD) affect bone metabolism and are frequently associated with the presence of osteoporosis. Bone loss is regulated by various mediators of the immune system such as the pro-inflammatory cytokines tumour necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), IL-6, or interferon-gamma. TNF-alpha, a master cytokine in human IBD, causes bone erosions in experimental models and these effects are exerted by osteoclasts. Other TNF-related cytokines such as receptor activator of nuclear factor kappa B (RANK), its ligand, RANKL, and osteoprotegerin are important mediators in inflammatory processes in the gut and are critically involved in the pathophysiology of bone loss. The awareness and early diagnosis of osteoporosis in states of chronic inflammation, together with applied therapies such as bisphosphonates, may be beneficial in inflammation-associated osteoporosis. Although several mechanisms may contribute to osteoporosis in patients with IBD and coeliac disease, inflammation as an important factor has so far been neglected. As key inflammatory mediators in IBD such as TNF-alpha are involved in the disease process both in gut and bone, we hypothesise that neutralisation of TNF-alpha could prove an efficient strategy in the treatment of inflammation-related osteoporosis in the future.

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“…Two major ways to overcome this problem have been described in literature. The first is based on the use of different human-derived cellular models and is widely used today [179,180], whereas the second is based on the use of ovariectomized cynomolgus monkeys. The latter model is based on the findings that human and monkey cathepsin K sequences are identical and that the expressed proteins exhibit indistinguishable enzymatic properties, and was introduced by the researchers from GlaxoSmithKline [181].…”

Section: Development Of Cathepsin K Inhibitors: a New Approach In Ostmentioning

confidence: 99%

Emerging Roles of Cysteine Cathepsins in Disease and their Potential as Drug Targets

Vasiljeva

Reinheckel²,

Peters³

et al. 2007

CPD

401

180

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The general view on cysteine cathepsins, which were long believed to be primarily involved in intracellular protein turnover, has dramatically changed in last 10 to 15 years. The discovery of new cathepsins, such as cathepsins K, V, X, F and O, and their tissue distribution suggested that at least some of them are involved in very specific cellular processes. Moreover, gene ablation experiments revealed that cathepsins play a vital role in numerous physiological processes, such as antigen processing and presentation, bone remodelling, prohormone processing and wound healing. Their involvement in several pathologies, including osteoporosis, rheumatoid arthritis, osteoarthritis, bronchial asthma and cancer have also been confirmed and today several of them have been validated as relevant targets for therapies. Compounds targeting cathepsins S and K are already in clinical evaluation, whereas others are in experimental phases. The cathepsin K inhibitor AAE-581 (balicatib) as the most advanced of them passed Phase II clinical trials in 2005. In this review, we discuss the current view on cathepsins as an emerging group of targets for several diseases and the development of cathepsin K and S inhibitors for treatment of osteoporosis and various immune disorders.

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SP500263, a novel SERM, blocks osteoclastogenesis in a human bone cell model: role of IL-6 and GM-CSF

Cited by 21 publications

References 62 publications

Human primary osteoclasts: in vitro generation and applications as pharmacological and clinical assay

Human primary osteoclasts: in vitro generation and applications as pharmacological and clinical assay

Gut, inflammation and osteoporosis: basic and clinical concepts

Emerging Roles of Cysteine Cathepsins in Disease and their Potential as Drug Targets

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