A peptidomimetic antagonist of the alpha(v)beta3 integrin inhibits bone resorption in vitro and prevents osteoporosis in vivo.

Engleman, V. Wayne; Nickols, G. Allen; Ross, F. Patrick; Horton, Michael A.; Griggs, David W.; Settle, Steven L.; Ruminski, Peter; Teitelbaum, Steven L.

doi:10.1172/jci119404

Cited by 271 publications

(191 citation statements)

References 42 publications

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“…In addition to reduced osteoblastic differentiation, it is possible that presentation of α V β 3 -selective ligands reduces overall bone formation by enhancing osteoclastic activity. Integrin α V β 3 is a major component of podosomes in the sealing zones of resorptive pits [32], and α V β 3 antagonists reduce bone resorption by reducing osteoclast activity [33][34][35]. However, we did not observe accumulation of multi-nucleated cells at the bone tissue-implant interface, suggesting that osteoclastic responses were not the dominant mechanism.…”

Section: Discussionmentioning

confidence: 62%

The effect of integrin-specific bioactive coatings on tissue healing and implant osseointegration

et al. 2008

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Implant osseointegration, defined as bone apposition and functional fixation, is a requisite for clinical success in orthopaedic and dental applications, many of which are restricted by implant loosening. Modification of implants to present bioactive motifs such as the RGD cell-adhesive sequence from fibronectin (FN) represents a promising approach in regenerative medicine. However, these biomimetic strategies have yielded only marginal enhancements in tissue healing in vivo. In this study, clinical-grade titanium implants were grafted with a non-fouling oligo(ethylene glycol)-substituted polymer coating functionalized with controlled densities of ligands of varying specificity for target integrin receptors. Biomaterials presenting the α 5 β 1 -integrin-specific FN fragment FNIII 7-10 enhanced osteoblastic differentiation in bone marrow stromal cells compared to unmodified titanium and RGD-presenting surfaces. Importantly, FNIII 7-10 -functionalized titanium significantly improved functional implant osseointegration compared to RGD-functionalized and unmodified titanium in vivo. This study demonstrates that bioactive coatings that promote integrin binding specificity regulate marrow-derived progenitor osteoblastic differentiation and enhance healing responses and functional integration of biomedical implants. This work identifies an innovative strategy for the rational design of biomaterials for regenerative medicine.

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Section: Discussionmentioning

confidence: 62%

The effect of integrin-specific bioactive coatings on tissue healing and implant osseointegration

et al. 2008

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“…Consequently, integrin ␣ v ␤ 3 and ␣ v ␤ 5 antagonists are promising therapeutic agents in diseases involving neovascularization, such as cancer, diabetic retinopathy, and rheumatoid arthritis. It should be noted that study of small molecule antagonists, like the one we have studied here for modification, typically suffer from poor pharmacokinetics and are typically administered in animal models at very high doses or by continuous pump-based delivery strategies (27)(28)(29)(30)(31)(32). Based on the cross-reactivity of the 38C2͞ SCS-873 complex with integrins ␣ v ␤ 3 and ␣ v ␤ 5 and the dual expression of integrins ␣ v ␤ 3 and ␣ v ␤ 5 on tumor cells and their supporting vasculature in some cancers, such as KS, melanoma, ovarian, and metastatic breast cancer, the 38C2͞SCS-873 complex is expected to direct multiple therapeutic strikes against cancer, with respect to both target and mechanism, with a single drug.…”

Section: Resultsmentioning

confidence: 99%

Chemically programmed monoclonal antibodies for cancer therapy: Adaptor immunotherapy based on a covalent antibody catalyst

Rader

Sinha

Popkov

et al. 2003

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

118

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Proposing that a blend of the chemical diversity of small synthetic molecules with the immunological characteristics of the antibody molecule will lead to therapeutic agents with superior properties, we here present a device that equips small synthetic molecules with both effector function and long serum half-life of a generic antibody molecule. As a prototype, we developed a targeting device that is based on the formation of a covalent bond of defined stoichiometry between a 1,3-diketone derivative of an integrin ␣v␤3 and ␣v␤5 targeting Arg-Gly-Asp peptidomimetic and the reactive lysine of aldolase antibody 38C2. The resulting complex was shown to (i) spontaneously assemble in vitro and in vivo, (ii) selectively retarget antibody 38C2 to the surface of cells expressing integrins ␣v␤3 and ␣v␤5, (iii) dramatically increase the circulatory half-life of the Arg-Gly-Asp peptidomimetic, and (iv) effectively reduce tumor growth in animal models of human Kaposi's sarcoma and colon cancer. This immunotherapeutic has the potential to target a variety of human cancers, acting on both the vasculature that supports tumor growth as well as the tumor cells themselves. Further, by use of a generic antibody molecule that forms a covalent bond with a 1,3-diketone functionality, essentially any compound can be turned into an immunotherapeutic agent thereby not only increasing the diversity space that can be accessed but also multiplying the therapeutic effect.

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“…These noncollagenous bone proteins are candidate ligands for the ␣ v ␤ 3 integrin expressed on the osteoclasts. In vitro data suggest that the ␤ 3 integrin subunit is involved in the attachment of osteoclasts to osteopontin and bone sialoprotein, whereas the ␤ 1 integrin subunit is responsible for the attachment of these cells to fibronectin (9). With regard to osteoclastic bone resorption in vitro, interactions between osteopontin and/or bone sialoprotein and the ␣ v ␤ 3 integrin (10,11) have been proposed to play a crucial role.…”

mentioning

confidence: 99%

Parathyroid Hormone-induced Bone Resorption Does Not Occur in the Absence of Osteopontin

Ihara¹,

Denhardt²,

Furuya³

et al. 2001

Journal of Biological Chemistry

106

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Osteopontin is an RGDS-containing protein that acts as a ligand for the ␣ v ␤ 3 integrin, which is abundantly expressed in osteoclasts, cells responsible for bone resorption in osteopenic diseases such as osteoporosis and hyperparathyroidism. However, the role of osteopontin in the process of bone resorption has not yet been fully understood. Therefore, we investigated the direct function of osteopontin in bone resorption using an organ culture system. The amount of 45 Ca released from the osteopontin-deficient bones was not significantly different from the basal release from wild type bones. However, in contrast to the parathyroid hormone (PTH) enhancement of the 45 Ca release from wild type bones, PTH had no effect on 45 Osteoclastic bone resorption is a key event in the pathophysiology of osteopenic diseases such as osteoporosis and hyperparathyroidism. Osteoclastic bone resorption involves a number of sequential events, including differentiation and activation of osteoclasts. These processes are regulated both by key cytokines and hormones interacting with various cell surface receptors and by interactions of osteoclast precursors with osteoblasts/stromal cells (1-3). The ␣ v ␤ 3 integrin is a major receptor on the osteoclast that can interact with RGD sequence-containing ligands such as osteopontin and vitronectin (4). It possibly promotes osteoclast attachment to bone and, when engaged by either immobilized or soluble ligands, stimulates signaling pathways that regulates osteoclast migration and function. Bone matrix consists of about 90% type I collagen and about 5% noncollagenous proteins. Among these noncollagenous proteins, at least five proteins, osteopontin, bone sialoprotein, thrombospondin, fibronectin, and vitronectin, contain RGD sequences that can be recognized by some integrins (5-8). These noncollagenous bone proteins are candidate ligands for the ␣ v ␤ 3 integrin expressed on the osteoclasts. In vitro data suggest that the ␤ 3 integrin subunit is involved in the attachment of osteoclasts to osteopontin and bone sialoprotein, whereas the ␤ 1 integrin subunit is responsible for the attachment of these cells to fibronectin (9). With regard to osteoclastic bone resorption in vitro, interactions between osteopontin and/or bone sialoprotein and the ␣ v ␤ 3 integrin (10, 11) have been proposed to play a crucial role. The signaling pathways stimulated by the integrin lead to modulation of cytoskeletal reorganization via regulatory molecules such as gelsolin (12). A recent study also indicates that the ␤ 3 integrin is important in osteoclastic bone resorption in vivo. (13) Osteopontin (14), is a mineralized matrix protein and a cytokine that has been suggested to act in several types of organs and systems, including bone (15), the immune system (16), the vascular system (17), and kidney (18). In addition, osteopontin is expressed at sites of inflammation. Osteopontin modifies cell behavior (19,20) and alters gene expression. In mineralized tissues, osteopontin is produced by osteoblasts and osteocla...

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A peptidomimetic antagonist of the alpha(v)beta3 integrin inhibits bone resorption in vitro and prevents osteoporosis in vivo.

Cited by 271 publications

References 42 publications

The effect of integrin-specific bioactive coatings on tissue healing and implant osseointegration

The effect of integrin-specific bioactive coatings on tissue healing and implant osseointegration

Chemically programmed monoclonal antibodies for cancer therapy: Adaptor immunotherapy based on a covalent antibody catalyst

Parathyroid Hormone-induced Bone Resorption Does Not Occur in the Absence of Osteopontin

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