Sclerostin: a possible target for the management of cancer-induced bone disease

Γκοτζαμανίδου, Μαρία; Dimopoulos, Meletios Α.; Kastritis, Efstathios; Christoulas, Dimitrios; Moulopoulos, Lia A.; Terpos, Evangelos

doi:10.1517/14728222.2012.697154

Cited by 31 publications

(30 citation statements)

References 66 publications

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“…Bone metastatic breast cancer cells may also express osteolytic “drivers” or transcription factors such as GLI2 and connective tissue growth factor (CTGF) that enhance secretion of osteolytic growth factors and cytokines [50]. Not content only with driving bone resorption, metastatic breast cancer cells also inhibit osteoblast differentiation through the RUNX2-dependent expression of sclerostin [76, 77]. This action disrupts the coupling of formation and resorption to facilitate unimpeded osteoclastic bone resorption resulting in the profound skeletal destruction characteristic of bone metastasis.…”

Section: Hallmarks Of Breast Cancer Bone Metastasismentioning

confidence: 99%

Hallmarks of Bone Metastasis

Johnson

Suva

2017

Calcif Tissue Int

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Breast cancer bone metastasis develops as the result of a series of complex interactions between tumor cells, bone marrow cells, and resident bone cells. The net effect of these interactions are the disruption of normal bone homeostasis, often with significantly increased osteoclast and osteoblast activity, which has provided a rational target for controlling tumor progression, with little or no emphasis on tumor eradication. Indeed, the clinical course of metastatic breast cancer is relatively long, with patients likely to experience sequential skeletal-related events (SREs), often over lengthy periods of time, even up to decades. These SREs include bone pain, fractures, and spinal cord compression, all of which may profoundly impair a patient’s quality-of-life. Our understanding of the contributions of the host bone and bone marrow cells to the control of tumor progression has grown over the years, yet the focus of virtually all available treatments remains on the control of resident bone cells, primarily osteoclasts. In this perspective, our focus is to move away from the current emphasis on the control of bone cells and focus our attention on the hallmarks of bone metastatic tumor cells and how these differ from primary tumor cells and normal host cells. In our opinion, there remains a largely unmet medical need to develop and utilize therapies that impede metastatic tumor cells while sparing normal host bone and bone marrow cells. This perspective examines the impact of metastatic tumor cells on the bone microenvironment and proposes potential new directions for uncovering the important mechanisms driving metastatic progression in bone based on the hallmarks of bone metastasis.

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Section: Hallmarks Of Breast Cancer Bone Metastasismentioning

confidence: 99%

Hallmarks of Bone Metastasis

Johnson

Suva

2017

Calcif Tissue Int

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“…Sclerostin may be a key mediator of cancer-induced bone disease and represents a promising therapeutic avenue for bone metastasis in breast cancer and myeloma-related bone disease 87 . Other targets include OPG, RANK/RANKL, cathepsin K, and other molecular pathways as potential emerging targets for metastatic bone pain 88,89 .…”

Section: Metastatic Bone Cancer and Cancer-induced Bone Lossmentioning

confidence: 99%

A Review of Osteocyte Function and the Emerging Importance of Sclerostin

Compton

Lee

2014

The Journal of Bone and Joint Surgery

157

112

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➤ Osteocytes, derived from osteoblasts, reside within bone and communicate extensively with other bone cell populations to regulate bone metabolism. The mature osteocyte expresses the protein sclerostin, a negative regulator of bone mass.➤ In normal physiologic states, the protein sclerostin acts on osteoblasts at the surface of bone and is differentially expressed in response to mechanical loading, inflammatory molecules such as prostaglandin E2, and hormones such as parathyroid hormone and estrogen.➤ Pathologically, sclerostin dysregulation has been observed in osteoporosis-related fractures, failure of implant osseous integration, metastatic bone disease, and select genetic diseases of bone mass.➤ An antibody that targets sclerostin, decreasing endogenous levels of sclerostin while increasing bone mineral density, is currently in phase-III clinical trials.➤ The osteocyte has emerged as a versatile, indispensable bone cell. Its location within bone, extensive dendritic network, and close communication with systemic circulation and other bone cells produce many opportunities to treat a variety of orthopaedic conditions.

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“…Sclerostin was initially identified as deficient in sclerosteosis, a disease of increased bone density [92]. Sclerostin is produced by osteocytes and impedes osteoblast proliferation and function, thereby increasing bone turnover as a result of reduced bone formation [91,93]. In vitro studies of metastatic breast cell lines with enhanced expression of sclerostin demonstrated increased ability to inhibit osteoblast function [94], supporting the hypothesis of a role for inhibition of sclerostin in the treatment of breast cancer-related metastases.…”

Section: Romosozumab/sclerostin Inhibitorsmentioning

confidence: 98%

“…Romosozumab is a humanized monoclonal anti-sclerostin antibody that has recently been shown to improve bone mineral density and bone formation in a Phase II study in post-menopausal women with low bone mineral density [90]. Sclerostin's role as a potential target for cancer-induced bone disease, specifically the osteolytic bone metastases seen in breast cancer, is currently under investigation [93].…”

Section: Romosozumab/sclerostin Inhibitorsmentioning

confidence: 99%

Pharmacotherapy of bone metastases in breast cancer patients – an update

Jacobs

Simos

Addison

et al. 2014

Expert Opinion on Pharmacotherapy

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Despite the potent osteoclast inhibiting effects of the bone-targeted agents in current clinical use, we have likely maximized their ability to inhibit SREs and must in turn focus on minimizing their potential toxicity. The future will likely involve more novel treatment strategies as well as the development of new agents. The current 'one size fits all' approach for the management of breast cancer bone metastases will be replaced by 'tailored' treatment for each individual patient as we usher in the era of 'personalized medicine.' In addition, new bone-targeted agents (e.g., sclerostin inhibitors) and combinations will continue to be explored, as will the evaluation of the bone-targeting properties of more conventional non-osteoclast targeting therapies.

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Sclerostin: a possible target for the management of cancer-induced bone disease

Cited by 31 publications

References 66 publications

Hallmarks of Bone Metastasis

Hallmarks of Bone Metastasis

A Review of Osteocyte Function and the Emerging Importance of Sclerostin

Pharmacotherapy of bone metastases in breast cancer patients – an update

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