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The Role Of Osteoclast Differentiation Factor TRANCE in Myeloma-Associated Bone Destruction
By Roger Pearse, MD, Ph.D, Memorial Sloan Kettering Cancer Ctr.
Roger Pearse, MD, Ph.D, Memorial Sloan Kettering Cancer Center
10.01.00
Bone destruction, caused by overactivity of osteoclasts, results in bone problems for over 80% of patients with multiple myeloma. TRANCE, a cytokine responsible for the production and survival of osteoclasts, has recently been identified and cloned. The goal of this project is to define the role of TRANCE in the development of myeloma associated bone destruction, and to investigate the potential efficacy of TRANCE antagonists to limit or prevent such bone destruction.

In normal individuals, bone is subject to continual remodelling, and bone deposition by osteoblasts is balanced by resorption by osteoclasts. In other words, osteoclasts destroy bone and osteoblasts repair it. Osteoblasts arise from mesenchymal stem cells in response to a variety of physical stimuli such as gravity, electricity, and magnetism, and chemical stimuli such as bone morphogenic proteins. Once mature, osteoblasts secrete a bone matrix comprised of fibrillar collagens, noncollagenous proteins and hydroxyapatite. As part of the coordinated remodelling process, mature osteoblasts also stimulate the production of osteoclasts from bone marrow hematopoetic stem cells of the monocytic lineage. In situ hybridization studies of mouse bone indicate this is accomplished by osteoblast expression of the cytokine TRANCE on their surfaces. Bone marrow stromal cells are also capable of TRANCE expression when stimulated by agents such as 1,25(OH)2vitaminD3, parathyroid hormone, or prostaglandin E2, and are thus also able to induce osteoclast differentiation. TRANCE binds to its receptor on the surface of monocytic stem cells to stimulate the expression of genes required for osteoclast development. As they mature, osteoclasts fuse into large, polarized, multinucleated syncytia which express the calcitonin receptor, tartrate resistant acid phosphatase, and integrin. Mature osteoclasts are capable of vectoral discharge of hydrogen ions, proteases, collagenases and cathepsins, all of which can destroy bone.

TRANCE, the osteoclast differentiating and activating factor, is a member of the TNF (Tumor Necrosis Factor) family of cytokines. TRANCE exists as both a 45kDa transmembrane protein and a 31kDa product of metalloproteinase cleavage from the cell surface. The TRANCE receptor expressed on osteoclasts is a 130kDa glycoprotein with strong homology to TNF receptor 2. As is common among receptors for TNF family members, intracellular signaling by the TRANCE receptor results in NF-KB activation through the activation of cytoplasmic TRAFs. However, unlike other TNF receptors, but similar to the other cytokine receptors, the TRANCE receptor also signals through activation of STATs (signal tranducers and activators of transcription). Further control of osteoclast production is provided by a soluble receptor for TRANCE to bind its transmembrane receptor on osteoclast precursors.

The cause of the increased osteoclast production seen in patients with multiple myeloma remains unknown. Several mediators, including lymphotoxin, IL-1B, Il-6, IL-11, TNF, and parathyroid hormone related protein, have been proposed as the osteoclast-activating factor (OAF) in multiple myeloma. However, none of these factors has been proven to be OAF, nor is any capable of stimulating the production of osteoclasts from their monocytic precursor. As TRANCE is necessary for osteoclastogenesis, and TRANCE expression appears to be increased in patients with multiple myeloma, I propose to study how myeloma cells regulate TRANCE expression and whether specific inhibition of TRANCE function will block or eliminate the ability of myeloma to destroy bone.


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