Extracellular Matrix Biology and Pathology

Role of Two Zinc Finger Proteins, ZFP521 and ZFP423

Faculty: Roland Baron, DDS, PhD
Investigators: Kei Yamana, PhD, visiting research fellow, principal investigator
Funder(s): Teijin Pharma Limited

This research focuses on the role of two zinc finger proteins (Zfp521 and Zfp423), which have been shown to play an important role in osteoblasts and chondrocytes and are induced by PTH, in the bone anabolic response to PTH in vivo and in vitro.

Role of the c-Src Proto-Oncogene in Osteoclasts

Funder(s): NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases

The aim of this multiyear study is to pursue our program identifying the function of c-Src that, in the osteoclast, is required for bone resorption (src- mutants develop osteopetrosis) and is unique to c-Src (i.e., cannot be compensated by other Src family of kinases in this cell). During the first 11 years of this program, we have made very significant progress toward understanding the functions of c-Src in bone resorption. Although the mechanism(s) by which src deletion leads...

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Regulation of Osteoclastic Bone Resorption: Role of Cb1b

Funder(s): NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases

In this study, we pursue our research on the molecular mechanisms of the differentiation of osteoclasts and bone resorption. The understanding osteoclast (OC) differentiation and activity has been revolutionized by the discovery that (1) the activation of RANK by RANK ligand is absolutely required for osteoclast formation and activity, and (2) stimulation of myelomonocytic precursors with M-CSF and RANK ligand is sufficient to induce the formation of OCs. Less publicized, but...

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Regulation of Osteoblast Differentiation by Delta FosB

Funder(s): NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases

The purpose of this study is to further understand how DeltaFosB (DFosB) increases bone formation (BF) in adult mice. Unlike most other transcription factors involved in osteoblast (OB) differentiation, DFosB increases BF postnatally, at any point in time, while not affecting skeletal development. This mimics the desired effects of a true bone anabolic therapeutic agent. We have now shown that the further truncated D2DFosB isoform recapitulates the phenotype of DFosB in bone....

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Pathophysiologic Regulation of FGF-23 in Phosphate Homeostasis: Role of Vitamin D

Investigators: Quan Yuan, PhD, Research Fellow, Michael Densmore, Research Associate
Funder(s): NIH/National Institute of Diabetes and Digestive and Kidney Diseases

Fibroblast growth factor-23 (FGF-23) is a recently identified molecule, which is implicated in the pathogenesis of various human diseases, including in X-linked hypophosphatemia (XLH), oncogenic osteomalacia (OOM), autosomal dominant hypophosphatemic rickets (ADHR), familial tumor calcinosis (FTC), and chronic renal diseases. FGF-23 is one of the most important and...

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Molecular Rationale for the Use of BMP2 in Bone Regeneration

Investigators: Giuseppe Intini, ITI fellow
Funder(s): ITI Foundation

With the major goal of describing the BMP2-dependent molecular mechanisms leading to bone regeneration, Dr. Intini will utilize the Bmp2c/c;Prx1:cre mutant mice, which display a limb specific inactivation of Bmp2, to identify the genetic networks, the signal pathways, and the target genes that are specifically activated in the presence of BMP2. Dr. Intini will take advantage of new molecular technologies such as individual mRNA barcoding, ChIP-on-Chip, and ChIP-seq...

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Molecular Mechanisms of Temporomandibular Joint Disorders by Use of Genetic and Nongenetic Mouse Models

Funder(s): The Eleanor and Miles Shore 50th Anniversary Fellowship Program for Scholars in Medicine

The objective of this research study focuses on the pathogenesis of temporomandibular joint disorders (TMJD) that affect millions of people around the world. Dr. Xu has identified two mutant mouse models for TMJD and established a surgically induced mouse TMJD model by partial discectomy. Dr. Xu has been investigating risk factors that are responsible for trauma-induced TMJD by use of these mouse models. Results from these studies will provide information for...

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Molecular Mechanisms of Choroidal Neovascularization and Vascular Homeostasis

Funder(s): NIH/NEI

Choroidal neovascularization (CNV) in age-related macular degeneration (AMD) is one of the leading causes of blindness worldwide. Our long-term goal is to elucidate the molecular mechanisms that regulate choroidal vascular development, choroidal vascular homeostasis in the adult, and CNV. Understanding these mechanisms is likely to provide the basis for a more targeted therapeutic approach in patients with neovascular AMD.

Recent experimental and clinical data have provided strong evidence for a pathogenetic role of VEGF signaling in...

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Molecular and Cellular Mechanisms of Vascular Anomalies

Funder(s): NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases

This program project (P01) aims to elucidate pathogenetic mechanisms of human vascular anomalies, to generate mouse models and identify therapeutic targets. These common vascular disorders belong to the group of childhood conditions popularly known as vascular birthmarks. One in about 100 children born have a vascular birthmark, and although significant progress has been made in identifying the genetic basis for many of the more rare forms of these anomalies, they are...

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Mechanism of Action of Halofuginone As a Novel Therapeutic

Investigators: Maja Edenius, PhD, Research Fellow, Chang-Yeol Yeo, PhD, Research Fellow
Funder(s): NIH/National Institute of Arthritis and Musculoskeletal and Skin Diseases

The use of small molecules to manipulate metabolic function in vivo has emerged as an important new approach to therapy for a wide range of disease pathologies. The amino acid starvation response (AAR) is a signaling pathway that controls a variety metabolic and cytoprotective functions in response to the restriction of amino acid availability. In our preliminary...

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Innovative Mouse Model to Study Parathyroids and an Application to Human Disease

Funder(s): NIH/National Institute of Diabetes and Digestive and Kidney Diseases

Parathyroid glands produce parathyroid hormone (PTH), one of the most important regulators of calcium and phosphate homeostasis, and of bone metabolism. FGF23, secreted from bone, is another crucial regulator of phosphate homeostasis. Recent data have suggested a bone-parathyroid axis in which FGF23 and PTH regulate each other; however, the existing data are contradictory and require clarification. Progress in understanding the molecular regulation of parathyroid cells is very slow...

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In Vivo Interactions of Fgf-23, Klotho, and Vitamin D

Funder(s): NIH/National Institute of Diabetes and Digestive and Kidney Diseases

Recent studies have shown crucial roles of fibroblast growth factor-23 (FGF-23) and klotho in regulating calcium and phosphate homeostasis. FGF-23 is an important in vivo regulator of phosphate homeostasis, while klotho is involved in regulating calcium homeostasis by interacting with the epithelial calcium channel transient receptor potential-vanilloid-5 (TRPV5). Interestingly, Fgf-23- and klotho-ablated (kl/kl, klotho-/-) mice have very similar physical, biochemical, and...

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Identification of Specific C-Cbl and Cbl-B Functions in Osteoclasts Biology

Investigators: Fabienne Coury, Research Fellow, principal investigator
Funder(s): Gideon and Sevgi Rodan Fellowship

The Gideon and Sevgi Rodan Fellowship from the International Bone and Mineral Society is given annually to support the research activities of a deserving young investigator in the bone field. Support is a one-year, nonrenewable grant. Dr. Coury received this fellowship based on her work on c-Cbl and Cbl-b, which are two widely expressed mammalian members of a family of adaptor proteins that are involved in various...

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Collagen gene structure and expression

Funder(s): NIH/NIAMS

The long-term goals of this project are to gain insights into mechanisms by which extracellular matrix components contribute to assembly, maintenance and function of vascular and epithelial tissues. The work is focused on a component of basement membranes, the specialized structures that separate epithelial and endothelial cells from underlying connective tissues. This component, collagen XVIII, interacts with other basement membrane constituents and receptors on adjacent cells via one of its domains, endostatin. In humans, recessive...

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BMP-3 signaling in the formation and regulation of bone

Funder(s): NIH/NIAMS

Although research on the bone morphogenetic proteins (BMPs) has expanded exponentially over the past decade, we actually know very little about the physiological roles that individual BMPs play in the skeleton. Our decision to focus this proposal on role the BMP3 in bone is based on several important findings. First, although BMP3 is the most abundant BMP in bone, accounting for 65% of the total BMP protein stored in bone matrix, little is known about its biology. A second reason for our interest in BMP3 are recent reports that correlate...

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