Pharmacologic Inhibition of the TGF-β Type I Receptor Kinase Has Anabolic and Anti-Catabolic Effects on Bone

Mohammad, Khalid S.; Chen, Carol G.; Balooch, Guive; Stebbins, Elizabeth G.; McKenna, Christopher R.; Davis, Holly W.; Niewolna, Maria; Xiang, Ping; Nguyen, Daniel H.; Ionova-Martin, Sophi S.; Bracey, John W.; Hogue, William R.; Wong, David G.; Ritchie, Robert O.; Suva, Larry J.; Derynck, Rik; Guise, Theresa A.; Alliston, Tamara

doi:10.1371/journal.pone.0005275

Cited by 174 publications

(184 citation statements)

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“…In addition, it impairs also adipogenesis, thus suggesting effects on a common progenitor cell [54]. TGFβ inhibition has potent anabolic effects [55] and restores osteogenesis in the presence of MM cellconditioned media and BM plasma from patients. It also suppresses MM cell growth.…”

Section: Pathogenesis Of Osteoblast Inhibition In MMmentioning

confidence: 99%

Bone Anabolic Agents for the Treatment of Multiple Myeloma

Vallet

2011

Cancer Microenvironment

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The majority of patients with multiple myeloma develop bone osteolytic lesions, which may lead to severe complications, including pain and fractures. The pathogenesis of bone disease depends on uncoupled bone remodeling, characterized by increased bone resorption due to upregulation of osteoclast activity and decreased bone formation due to osteoblast inhibition. In myeloma, impaired osteoblast differentiation and increased apoptosis have been described. Responsible for these effects are integrin-mediated adhesion to tumor cells and soluble factors, including WNT antagonists, BMP2 inhibitors and numerous cytokines. Based on the evidence of osteoblast suppression in myeloma, bone anabolic agents have been developed and are currently undergoing clinical evaluation. Due to bidirectional inhibitory effects characterizing tumor cells and osteoblasts interactions, agents targeting osteoblasts are expected to reduce tumor burden along with improvement of bone health. This review summarizes the current knowledge on osteoblast inhibition in myeloma and provides an overview on the clinical grade agents with bone anabolic properties, which represent new promising therapeutic strategies in myeloma.

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Section: Pathogenesis Of Osteoblast Inhibition In MMmentioning

confidence: 99%

Bone Anabolic Agents for the Treatment of Multiple Myeloma

Vallet

2011

Cancer Microenvironment

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“…Tumor-produced factors such as parathyroid hormone-related protein (PTHrP), interleukin-11 (IL-11), IL-6, and IL-8 stimulate bone resorption to release and activate growth factors housed in the mineralized bone matrix. Bone-derived TGF-b promotes osteolysis by stimulating tumor production of osteolytic factors, and alters the bone microenvironment to further increase osteoclastic bone resorption and inhibit bone formation Korpal et al 2009;Mohammad et al 2009). These tumor-bone interactions result in a feed-forward cycle to promote tumor growth in bone.…”

mentioning

confidence: 99%

Breaking down bone: new insight into site-specific mechanisms of breast cancer osteolysis mediated by metalloproteinases: Figure 1.

Guise

2009

Genes Dev.

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Bone metastases are the most common skeletal complication of malignancy. Tumor cells disrupt normal bone remodeling to promote bone destruction and its associated morbidity. In the August 15, 2009, issue of Genes & Development, Lu and colleagues (pp. 1882-1894) propose a novel molecular mechanism by which tumor-produced metalloproteinases release epidermal growth factor (EGF) ligands to activate the central osteoclastogenic pathway receptor activator of NF-kB ligand (RANKL) to promote breast cancer osteolysis. This work has important therapeutic applications that may quickly translate to more effective treatment for bone metastases.Bone metastases are common in breast, prostate, and lung cancer, and are associated with significant morbidity. Unique aspects of the bone microenvironment-such as mineralized bone matrix, which houses immobilized growth factors, bone-destroying osteoclasts, and boneforming osteoblasts-make it a fertile soil for these cancers to grow. Significant insight into the molecular mechanisms responsible for the proclivity of tumors to metastasize and grow in bone has been gleaned in recent years from mouse models and clinical studies. Bone destruction mediated by solid tumor metastases to bone, particularly in breast cancer, is driven by tumor stimulation of osteoclastic bone resorption. Collective evidence supports the notion that effective therapy for bone metastases should target both the tumor and the bone microenvironment. Indeed, bisphosphonate therapy to block osteoclastic bone resorption, used in conjunction with standard anti-cancer treatments, reduces bone pain, pathologic fracture, and hypercalcemia associated with bone metastases from all tumor types. However, regression and cure of bone metastases have yet to be achieved with the current therapeutic armamentarium. Thus, a better understanding of the molecular mechanisms responsible for this devastating skeletal complication of malignancy is required to develop more effective therapy, with the eventual goal of curing and preventing bone metastases. In the August 15, 2009, issue of Genes & Development, Lu et al. (2009) bring the field closer to this goal. They describe an autocrine/paracrine signaling cascade triggered by metalloproteinases-matrix metalloproteinase-1 (MMP-1) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS1)-and cleavage of epidermal growth factor (EGF) ligands to reduce the ratio of osteoblast-produced receptor activator of NF-kB ligand (RANKL) to osteoprotegerin (OPG) to favor osteoclastogenesis and promote breast cancer osteolysis. These studies, described herein, have important implications for new applications of standard cancer therapy that could result in more effective treatment for bone metastases. Bone metastases: clinical features and current therapyCertain solid tumors-such as breast, prostate, and lung cancer-have a propensity to metastasize to bone to cause bone pain, fracture, hypercalcemia, and paralysis. This morbidity is great: Up to 75% of advanced breast and prostate c...

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“…In multiple myeloma, TGF-β is secreted by myeloma and bone marrow stromal cells (19,20). TGF-β is an important factor during the disease development, which involves a complex signaling pathway network.…”

Section: Discussionmentioning

confidence: 99%

TGF-β induces growth suppression in multiple myeloma MM.1S cells via E2F1

Liu¹,

Guo²,

Wei³

et al. 2017

Oncology Letters

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Abstract. Transforming growth factor-β (TGF-β) has an important role in multiple target genes and signaling pathways. The E2F family of transcription factors is a group of DNA-binding proteins that are involved in cell-cycle progression, and therefore have a key role in proliferation. The present study demonstrates that inhibition of cell growth by TGF-β occurs in the multiple myeloma cell line MM.1S. However, the growth-suppressive effects of TGF-β may be reversed by small interfering (si)RNA to reduce the expression of E2F1. TGF-β1 and E2F1 siRNA were manipulated in MM.1S cells to investigate the association between these genes. FACScan Flow Cytometer, western blot analysis and other methods were adopted to confirm such interrelation. The present data showed that TGF-β mediated growth suppression in MM.1S cells, while inducing E2F1 protein expression levels rapidly and transiently. The present data support the hypothesis that E2F1 is a central mediator of TGF-β-induced growth suppression in MM.1S cells and control of E2F1 may be a downstream event of TGF-β action, at least in one multiple myeloma cell line.

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Pharmacologic Inhibition of the TGF-β Type I Receptor Kinase Has Anabolic and Anti-Catabolic Effects on Bone

Cited by 174 publications

References 50 publications

Bone Anabolic Agents for the Treatment of Multiple Myeloma

Bone Anabolic Agents for the Treatment of Multiple Myeloma

Breaking down bone: new insight into site-specific mechanisms of breast cancer osteolysis mediated by metalloproteinases: Figure 1.

TGF-β induces growth suppression in multiple myeloma MM.1S cells via E2F1

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