Paloma Valverde, Ph.D.
Research Scientist
bone-loss associated diseases, therapies, RANKL, BSP, SIBLING, WW45
Email: valverde at bbri.org

Research Summary
The process of bone remodeling is important to maintain a careful balance between bone resorption by osteoclasts and bone formation by osteoblasts and lead to normal bone homeostasis. A variety of cytokines, extracellular matrix proteins, and hormones have been shown to regulate osteoclastic and/or osteoblastic activities. Among these factors, receptor activator of nuclear factor-NFkB ligand (RANKL), its cellular receptor, RANK, and the decoy receptor, osteoprotegerin (OPG) have been identified as the key regulators of physiological and pathological bone remodeling. Upon binding to its receptor RANK in osteoclasts, RANKL induces osteoclast differentiation and activation which in turn increases bone resorption. In contrast, OPG inhibits bone resorption by osteoclasts through negatively regulating the binding between RANKL and RANK. Bone sialoprotein (BSP) is an extracellular matrix protein of the SIBLING family produced by osteoclasts, osteoblasts and cancer cells. Several bone loss-associated diseases, including postmenopausal osteoporosis or metastatic breast cancer have been associated with abnormally high BSP and RANKL levels in serum. Our previous in vitro and in vivo studies have suggested BSP increase RANKL-induced osteoclastogenesis and inhibit osteoclast apoptosis leading to excessive bone loss. To develop new therapeutics for these patients it is necessary to carefully characterize the signaling mediators of BSP and RANKL effects in osteoclasts. To that end we plan to use membrane-permeable peptides targeting inducers of osteoclastogenesis and inhibitors of apoptosis that are up-regulated in BSP/RANKL-treated osteoclasts. Alternatively, signaling mediators of apoptosis that are down-regulated by BSP/RANKL will be rescued by using recombinant proteins engineered to contain cell-permeable sequences.

Selected Publications
Valverde P, Zhang J, Fix A, Zhu J, Ma W, Tu Q, Chen J. (2008) Overexpression of Bone Sialoprotein Leads to an Uncoupling of Bone Formation and Bone Resorption in Mice. J Bone Miner Res. Jul 2. [Epub ahead of print]
PMID: 18597627

Valverde P. (2008) Pharmacotherapies to manage bone loss-associated diseases: a quest for the perfect benefit-to-risk ratio. Curr Med Chem. 15(3):284-304. Review.
PMID: 18288984

Tu Q, Valverde P, Li S, Zhang J, Yang P, Chen J. (2007) Osterix overexpression in mesenchymal stem cells stimulates healing of critical-sized defects in murine calvarial bone. Tissue Eng. 13(10):2431-40.
PMID: 17630878

Valverde P, Tu Q, Chen J. (2005) BSP and RANKL induce osteoclastogenesis and bone resorption synergistically. J Bone Miner Res. 20(9):1669-79.
PMID: 16059638

Valverde P, Kawai T, Taubman MA. (2004) Selective blockade of voltage-gated potassium channels reduces inflammatory bone resorption in experimental periodontal disease. J Bone Miner Res. 19(1):155-64.
PMID: 14753747

Valverde P. (2000) Cloning, expression, and mapping of hWW45, a novel human WW domain-containing gene. Biochem Biophys Res Commun. 276(3):990-8.
PMID: 11027580

PubMed:
Click here for a list of publications (searches the National Library of Medicine's PubMed database.)