Targeting Sclerostin in Postmenopausal Osteoporosis: Focus on Romosozumab and Blosozumab

Reid, Ian R.

doi:10.1007/s40259-017-0229-2

Cited by 16 publications

(12 citation statements)

References 38 publications

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“…Excessive GC has been shown to stimulate sclerostin secretion from osteocytes. Neutralizing antibodies against sclerostin, such as romosozumab, can promote Wnt signaling and improve osteoblast function [172]. Elsewhere, it has been reported that miR-29a can suppress the side effects of excessive GCs on osteoblast differentiation in vitro and restore Wnt signaling by regulating β-catenin acetylation [173].…”

Section: Conclusion and Perspectivementioning

confidence: 99%

The shift in the balance between osteoblastogenesis and adipogenesis of mesenchymal stem cells mediated by glucocorticoid receptor

et al. 2019

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Mesenchymal stem cells (MSCs) are multipotent cells capable of differentiating into several tissues, such as bone, cartilage, and fat. Glucocorticoids affect a variety of biological processes such as proliferation, differentiation, and apoptosis of various cell types, including osteoblasts, adipocytes, or chondrocytes. Glucocorticoids exert their function by binding to the glucocorticoid receptor (GR). Physiological concentrations of glucocorticoids stimulate osteoblast proliferation and promote osteogenic differentiation of MSCs. However, pharmacological concentrations of glucocorticoids can not only induce apoptosis of osteoblasts and osteocytes but can also reduce proliferation and inhibit the differentiation of osteoprogenitor cells. Several signaling pathways, including the Wnt, TGFβ/BMP superfamily and Notch signaling pathways, transcription factors, post-transcriptional regulators, and other regulators, regulate osteoblastogenesis and adipogenesis of MSCs mediated by GR. These signaling pathways target key transcription factors, such as Runx2 and TAZ for osteogenesis and PPARγ and C/EBPs for adipogenesis. Glucocorticoid-induced osteonecrosis and osteoporosis are caused by various factors including dysfunction of bone marrow MSCs. Transplantation of MSCs is valuable in regenerative medicine for the treatment of osteonecrosis of the femoral head, osteoporosis, osteogenesis imperfecta, and other skeletal disorders. However, the mechanism of inducing MSCs to differentiate toward the osteogenic lineage is the key to an efficient treatment. Thus, a better understanding of the molecular mechanisms behind the imbalance between GR-mediated osteoblastogenesis and adipogenesis of MSCs would not only help us to identify the pathogenic causes of glucocorticoid-induced osteonecrosis and osteoporosis but also promote future clinical applications for stem cell-based tissue engineering and regenerative medicine. Here, we primarily review the signaling mechanisms involved in adipogenesis and osteogenesis mediated by GR and discuss the factors that control the adipo-osteogenic balance.

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Section: Conclusion and Perspectivementioning

confidence: 99%

The shift in the balance between osteoblastogenesis and adipogenesis of mesenchymal stem cells mediated by glucocorticoid receptor

et al. 2019

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“…Demonstration of SOST expression by multiple cell types and identification of SOST as an evolutionarily conserved key player in bone modeling in fishes expands the relevance of sclerostin to modeling regulation for both paracrine and autocrine signaling. Currently, a wave of new sclerostin-targeting therapies are being explored in an effort to control sclerostin’s antianabolic properties in the treatment of osteoporosis and other skeletal disorders [42–44]. Our findings suggest great potential for the massively speciose clade of fishes, with both osteocytic and anosteocytic members, as a powerful and relevant platform for research in bone physiology, as well as fracture healing and bone therapeutics.…”

Section: Discussionmentioning

confidence: 91%

A novel nonosteocytic regulatory mechanism of bone modeling

et al. 2019

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Osteocytes, cells forming an elaborate network within the bones of most vertebrate taxa, are thought to be the master regulators of bone modeling, a process of coordinated, local bone-tissue deposition and removal that keeps bone strains at safe levels throughout life. Neoteleost fish, however, lack osteocytes and yet are known to be capable of bone modeling, although no osteocyte-independent modeling regulatory mechanism has so far been described. Here, we characterize a novel, to our knowledge, bone-modeling regulatory mechanism in a fish species (medaka), showing that although lacking osteocytes (i.e., internal mechanosensors), when loaded, medaka bones model in mechanically directed ways, successfully reducing high tissue strains. We establish that as in mammals, modeling in medaka is regulated by the SOST gene, demonstrating a mechanistic link between skeletal loading, SOST down-regulation, and intense bone deposition. However, whereas mammalian SOST is expressed almost exclusively by osteocytes, in both medaka and zebrafish (a species with osteocytic bones), SOST is expressed by a variety of nonosteocytic cells, none of which reside within the bone bulk. These findings argue that in fishes (and perhaps other vertebrates), nonosteocytic skeletal cells are both sensors and responders, shouldering duties believed exclusive to osteocytes. This previously unrecognized, SOST -dependent, osteocyte-independent mechanism challenges current paradigms of osteocyte exclusivity in bone-modeling regulation, suggesting the existence of multivariate feedback networks in bone modeling—perhaps also in mammalian bones—and thus arguing for the possibility of untapped potential for cell targets in bone therapeutics.

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“…Sclerostin is a soluble protein secreted from osteocytes that differentiated from osteoblasts, which prevents Wnt from binding to low-density lipoprotein receptor-related proteins-5/6 transmembrane receptors [60]. This blockade prevents osteoblast differentiation to inhibit bone formation [60,61]. In a recent study, higher circulating sclerostin levels were observed in patients with advanced liver cirrhosis than in healthy controls or patients with early liver cirrhosis [62].…”

Section: Pathogenesismentioning

confidence: 99%

Bone Diseases in Patients with Chronic Liver Disease

Jeong

Kim

2019

IJMS

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Osteoporosis is a frequently observed complication in patients with chronic liver disease, particularly liver cirrhosis and cholestatic liver diseases. In addition, osteoporosis is critical in patients receiving a liver transplant. Nevertheless, few studies have evaluated bone diseases in patients with more frequently observed chronic liver disease, such as chronic viral hepatitis, nonalcoholic fatty liver disease and alcoholic liver disease. Osteoporosis is a disease caused by an imbalance in the activities of osteoblasts and osteoclasts. Over the last few decades, many advances have improved our knowledge of the pathogenesis of osteoporosis. Importantly, activated immune cells affect the progression of osteoporosis, and chronic inflammation may exert an additional effect on the existing pathophysiology of osteoporosis. The microbiota of the intestinal tract may also affect the progression of bone loss in patients with chronic liver disease. Recently, studies regarding the effects of chronic inflammation on dysbiosis in bone diseases have been conducted. However, mechanisms underlying osteoporosis in patients with chronic liver disease are complex and precise mechanisms remain unknown. The following special considerations in patients with chronic liver disease are reviewed: bone diseases in patients who underwent a liver transplant, the association between chronic hepatitis B virus infection treatment and bone diseases, the association between sarcopenia and bone diseases in patients with chronic liver disease, and the association between chronic liver disease and avascular necrosis of the hip. Few guidelines are currently available for the management of low bone mineral density or bone diseases in patients with chronic liver disease. Due to increased life expectancy and therapeutic advances in chronic liver disease, the importance of managing osteoporosis and other bone diseases in patients with chronic liver disease is expected to increase. Consequently, specific guidelines need to be established in the near future.

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Targeting Sclerostin in Postmenopausal Osteoporosis: Focus on Romosozumab and Blosozumab

Cited by 16 publications

References 38 publications

The shift in the balance between osteoblastogenesis and adipogenesis of mesenchymal stem cells mediated by glucocorticoid receptor

The shift in the balance between osteoblastogenesis and adipogenesis of mesenchymal stem cells mediated by glucocorticoid receptor

A novel nonosteocytic regulatory mechanism of bone modeling

Bone Diseases in Patients with Chronic Liver Disease

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