New therapeutic targets for osteoporosis: Beyond denosumab

Lim, Vivien; Clarke, B.L.

doi:10.1016/j.maturitas.2012.08.002

Cited by 25 publications

(15 citation statements)

References 28 publications

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“…Accordingly, current clinical applications for osteoporosis target Wnt inhibitors to stimulate formation of new bone and inhibit bone resorption, or so-called “inhibitors to Wnt inhibitors.” Currently targeted Wnt signaling antagonists include Sclerostin (SOST) and Dickkopf-1 (DKK1) [115]. Expectedly, inhibition of these antagonists, via anti-SOST and anti-DKK1, respectively, has been shown to stimulate bone formation and increase bone mineral density, with phase II clinical trials (for anti-SOST) and preclinical trials (for anti-DKK1) underway [116–118]…”

Section: Control Of Adipogenesis and Osteogenesis By Wnt Signalingmentioning

confidence: 99%

Review of Signaling Pathways Governing MSC Osteogenic and Adipogenic Differentiation

2013

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Mesenchymal stem cells (MSC) are multipotent cells, functioning as precursors to a variety of cell types including adipocytes, osteoblasts, and chondrocytes. Between osteogenic and adipogenic lineage commitment and differentiation, a theoretical inverse relationship exists, such that differentiation towards an osteoblast phenotype occurs at the expense of an adipocytic phenotype. This balance is regulated by numerous, intersecting signaling pathways that converge on the regulation of two main transcription factors: peroxisome proliferator-activated receptor-γ (PPARγ) and Runt-related transcription factor 2 (Runx2). These two transcription factors, PPARγ and Runx2, are generally regarded as the master regulators of adipogenesis and osteogenesis. This review will summarize signaling pathways that govern MSC fate towards osteogenic or adipocytic differentiation. A number of signaling pathways follow the inverse balance between osteogenic and adipogenic differentiation and are generally proosteogenic/antiadipogenic stimuli. These include β-catenin dependent Wnt signaling, Hedgehog signaling, and NELL-1 signaling. However, other signaling pathways exhibit more context-dependent effects on adipogenic and osteogenic differentiation. These include bone morphogenic protein (BMP) signaling and insulin growth factor (IGF) signaling, which display both proosteogenic and proadipogenic effects. In summary, understanding those factors that govern osteogenic versus adipogenic MSC differentiation has significant implications in diverse areas of human health, from obesity to osteoporosis to regenerative medicine.

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Section: Control Of Adipogenesis and Osteogenesis By Wnt Signalingmentioning

confidence: 99%

Review of Signaling Pathways Governing MSC Osteogenic and Adipogenic Differentiation

2013

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“…Several new therapeutic targets for building bone have profoundly changed our understanding as to why age-related bone loss occurs. Two inhibitory proteins, known as sclerostin (Burgers & Williams, 2013) and Dickkopf-1 (DKK1), have been identified and both proteins interact with the Wnt coreceptors LRP5/6 to inhibit the canonical Wnt/beta-catenin signaling pathway, causing a decrease in bone formation (Moester et al, 2010;Palaniswamy et al, 2010;Paszty et al, 2010;Lewiecki, 2011;Costa & Bilezikian, 2012;Ke et al, 2012;Lim & Clarke, 2012;Ohlsson, 2013). DKK1 appears to have a greater role in developing animals than in adults (Ke et al, 2012).…”

Section: Anabolic Therapies and Skeletal Painmentioning

confidence: 99%

The neurobiology of skeletal pain

Mantyh

2014

Eur J of Neuroscience

156

158

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Disorders of the skeleton are one of the most common causes of chronic pain and long-term physical disability in the world. Chronic skeletal pain is caused by a remarkably diverse group of conditions including trauma-induced fracture, osteoarthritis, osteoporosis, low back pain, orthopedic procedures, celiac disease, sickle cell disease and bone cancer. While these disorders are diverse, what they share in common is that when chronic skeletal pain occurs in these disorders, there are currently few therapies that can fully control the pain without significant unwanted side effects. In this review we focus on recent advances in our knowledge concerning the unique population of primary afferent sensory nerve fibers that innervate the skeleton, the nociceptive and neuropathic mechanisms that are involved in driving skeletal pain, and the neurochemical and structural changes that can occur in sensory and sympathetic nerve fibers and the CNS in chronic skeletal pain. We also discuss therapies targeting nerve growth factor or sclerostin for treating skeletal pain. These therapies have provided unique insight into the factors that drive skeletal pain and the structural decline that occurs in the aging skeleton. We conclude by discussing how these advances have changed our understanding and potentially the therapeutic options for treating and/or preventing chronic pain in the injured, diseased and aged skeleton. GRAPHICAL ABSTRACT: Skeletal pain is common and frequently difficult to fully control. Recent data suggests that the skeleton is innervated by a restricted set of nociceptors and that many skeletal pains have both a nociceptive and a neuropathic component. Significant progress has been made in defining the mechanisms that drive skeletal pain and the factors that control skeletal remodeling. These insights have the potential to fundamentally transform our understanding and ability to prevent and/or treat skeletal pain due to injury, disease, and aging.

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“…Future treatments for osteoporosis include cathepsin K inhibitors which appear to have mixed antiresorptive and anabolic actions as they inhibit one of the major osteoclast digestive enzymes without suppressing bone formation, thereby leading to anabolic effects on bone [39]. New biologic agents in clinical trials include anti-sclerostin and anti-dickkopf antibodies that stimulate the Wnt/␤-catenin pathway in osteoblasts, leading to new bone formation [40].…”

Section: Conserving the Skeleton And Musculoskeletal Healthmentioning

confidence: 99%