Inhibition of TGF-β signaling by 1D11 antibody treatment increases bone mass and quality in vivo

Edwards, James; Nyman, Jeffry S.; Lwin, Seint T.; Moore, Megan; Esparza, J.; O'Quinn, Elizabeth C; Hart, A.; Biswas, Swati; Patil, Chetan A.; Lonning, Scott; Mahadevan‐Jansen, Anita; Mundy, Gregory R.

doi:10.1002/jbmr.139

Cited by 102 publications

(127 citation statements)

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“…Consistent with a previous report by Edwards et al (4), our data show that 1D11 treatment in WT mice for 4 wk resulted in a significant accrual of trabecular bone in L4 vertebra (Fig. 5C), as evidenced by a 37.8% increase in BV/TV (26.7% of the placebo group vs. 35.4% of the 1D11-treated group).…”

Section: Resultssupporting

confidence: 93%

“…It plays a crucial role in regulating the differentiation of both OBs and OCs and mediating OB-OC coupling during bone remodeling (2,3). Therefore, manipulating TGF-β signaling in bone offers an attractive strategy for the treatment of bone diseases, such as osteoporosis and osteolytic bone metastasis of cancers (4,5). Recent data show that TGF-β can play either a catabolic or anabolic role in bone homeostasis, suggesting that TGF-β signaling acts in a context-and dose-dependent manner (4,(6)(7)(8)(9)(10).…”

mentioning

confidence: 99%

“…Therefore, manipulating TGF-β signaling in bone offers an attractive strategy for the treatment of bone diseases, such as osteoporosis and osteolytic bone metastasis of cancers (4,5). Recent data show that TGF-β can play either a catabolic or anabolic role in bone homeostasis, suggesting that TGF-β signaling acts in a context-and dose-dependent manner (4,(6)(7)(8)(9)(10). This emphasizes the need for a precise regulation of TGF-β bioavailability to maintain balanced bone remodeling.…”

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confidence: 99%

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E-selectin ligand 1 regulates bone remodeling by limiting bioactive TGF-β in the bone microenvironment

Yang

Grafe

Bae

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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TGF-β is abundantly produced in the skeletal system and plays a crucial role in skeletal homeostasis. E-selectin ligand-1 (ESL-1), a Golgi apparatus-localized protein, acts as a negative regulator of TGF-β bioavailability by attenuating maturation of pro-TGF-β during cartilage homeostasis. However, whether regulation of intracellular TGF-β maturation by ESL-1 is also crucial during bone homeostasis has not been well defined. Here, we show that Esl-1 −/− mice exhibit a severe osteopenia with elevated bone resorption and decreased bone mineralization. In primary culture, Esl-1 −/− osteoclast progenitors show no difference in osteoclastogenesis. However, Esl-1 −/− osteoblasts show delayed differentiation and mineralization and stimulate osteoclastogenesis more potently in the osteoblast-osteoclast coculture, suggesting that ESL-1 primarily acts in osteoblasts to regulate bone homeostasis. In addition, Esl-1 −/− calvaria exhibit an elevated mature TGF-β/pro-TGF-β ratio, with increased expression of TGF-β downstream targets (plasminogen activator inhibitor-1, parathyroid hormone-related peptide, connective tissue growth factor, and matrix metallopeptidase 13, etc.) and a key regulator of osteoclastogenesis (receptor activator of nuclear factor κB ligand). Moreover, in vivo treatment with 1D11, a pan-TGF-β antibody, significantly improved the low bone mass of Esl-1 −/− mice, suggesting that elevated TGF-β signaling is the major cause of osteopenia in Esl-1 −/− mice. In summary, our study identifies ESL-1 as an important regulator of bone remodeling and demonstrates that the modulation of TGF-β maturation is pivotal in the maintenance of a homeostatic bone microenvironment and for proper osteoblast-osteoclast coupling.1D11 antibody | osteoblast mineralization | osteoporosis

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Section: Resultssupporting

confidence: 93%

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confidence: 99%

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confidence: 99%

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E-selectin ligand 1 regulates bone remodeling by limiting bioactive TGF-β in the bone microenvironment

Yang

Grafe

Bae

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

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“…55,56 In the first mouse study, 13-week-old male mice (FVB strain) were treated with either a TGF-b-neutralizing antibody (1D11, n ¼ 8) or a control antibody (13C4, n ¼ 7) for 4 weeks at the same dose (10 mg kg À 1 3x per week) because inhibiting TGF-b increases BV/TV 57 and, hence, would be expected to increase VB compressive strength. In the second study, activating transcription factor 4-null (Atf4 À / À ) mice (n ¼ 10) and their wild-type littermates (n ¼ 10) were euthanized at 17 weeks of age (male and female on a FVB background).…”

Section: Methodsmentioning

confidence: 99%

Predicting mouse vertebra strength with micro-computed tomography-derived finite element analysis

Nyman¹,

Uppuganti²,

Makowski³

et al. 2015

BoneKEy Reports

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As in clinical studies, finite element analysis (FEA) developed from computed tomography (CT) images of bones are useful in pre-clinical rodent studies assessing treatment effects on vertebral body (VB) strength. Since strength predictions from microCT-derived FEAs (mFEA) have not been validated against experimental measurements of mouse VB strength, a parametric analysis exploring material and failure definitions was performed to determine whether elastic mFEAs with linear failure criteria could reasonably assess VB strength in two studies, treatment and genetic, with differences in bone volume fraction between the control and the experimental groups. VBs were scanned with a 12-mm voxel size, and voxels were directly converted to 8-node, hexahedral elements. The coefficient of determination or R 2 between predicted VB strength and experimental VB strength, as determined from compression tests, was 62.3% for the treatment study and 85.3% for the genetic study when using a homogenous tissue modulus (E t ) of 18 GPa for all elements, a failure volume of 2%, and an equivalent failure strain of 0.007. The difference between prediction and measurement (that is, error) increased when lowering the failure volume to 0.1% or increasing it to 4%. Using inhomogeneous tissue density-specific moduli improved the R 2 between predicted and experimental strength when compared with uniform E t ¼ 18 GPa. Also, the optimum failure volume is higher for the inhomogeneous than for the homogeneous material definition. Regardless of model assumptions, mFEA can assess differences in murine VB strength between experimental groups when the expected difference in strength is at least 20%.

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“…In addition to direct effects on the tumor, treatement of healthy (i.e., tumor-free) mice with the TGF-β inhibitors 1D11 (Genzyme, Cambridge, MA) and SD-208 (Scios, Inc., Sunnyvale, CA) increases bone density and biomechanical properties as well as numerous measures of bone quality (e.g., trabecular bone architecture and mineral: collagen ratio) [114,115]. Blocking TGF-β also increased the numbers of osteoblasts and decreased the numbers of osteoclasts in the bone marrow of healthy mice.…”

Section: Clinical Perspectivesmentioning

confidence: 99%

Contribution of Bone Tissue Modulus to Breast Cancer Metastasis to Bone

Guelcher

Sterling

2011

Cancer Microenvironment

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Certain tumors, such as breast, frequently metastasize to bone where they can induce bone destruction. Currently, it is well-accepted that the tumor cells are influenced by other cells and growth factors present in the bone microenvironment that lead to tumor-induced bone disease. Over the past 20 years, many groups have studied this process and determined the major contributing factors; however, these results do not fully explain the changes in gene expression and cell behavior that occur when tumor cells metastasize to bone. More recently, groups studying metastasis from soft tissue sites have determined that the rigidity of the microenvironment, which increases during tumor progression in soft tissue, can regulate tumor cell behavior and gene expression. Therefore, we began to investigate the role of the rigid bone extracellular matrix in the regulation of genes that stimulate tumor-induced bone disease. We found that the rigidity of bone specifically regulates parathyroid hormone-related protein (PTHrP) and Gli2 expression in a transforming growth factor β (TGF-β) and mechanotransduction-dependent mechanism. In this review, we summarize the mechanotransduction signaling pathway and how this influences TGF-β signaling and osteolytic gene expression.

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Inhibition of TGF-β signaling by 1D11 antibody treatment increases bone mass and quality in vivo

Cited by 102 publications

References 30 publications

E-selectin ligand 1 regulates bone remodeling by limiting bioactive TGF-β in the bone microenvironment

E-selectin ligand 1 regulates bone remodeling by limiting bioactive TGF-β in the bone microenvironment

Predicting mouse vertebra strength with micro-computed tomography-derived finite element analysis

Contribution of Bone Tissue Modulus to Breast Cancer Metastasis to Bone

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