Developmental 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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Role of Indian Hedgehog in Endochondral Bone Formation

Investigators: Yukiko Maeda, PhD, research associate; Dutmanee Seriwatanachai, PhD,research fellow; Michael Densmore, research associate
Funder(s): NIH/National Institute of Diabetes and Digestive and Kidney Diseases

Indian hedgehog (Ihh) has multiple functions during skeletogenesis. Mice lacking the Ihh gene exhibit severe skeletal abnormalities, including markedly reduced chondrocyte proliferation and abnormal maturation, with absence of mature osteoblasts. Since Ihh and its receptor, smoothened (smo), are expressed in chondrocytes as...

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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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In Vivo Analyses of Fibroblast Growth Factor-23 Function

A major focus of our research is to determine the roles and interactions of key molecules controlling mineral homeostasis, particularly phosphate homeostasis. Phosphate is essential, not only for signaling and energy metabolism, but also for normal skeletal growth and development. Disturbances in phosphate homeostasis can affect the functional activities of almost any organ system.

Despite its wide biological importance and significance, the regulation of phosphate homeostasis is not yet clearly understood. Recent studies have identified a number of molecules that have phosphaturic...

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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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