Funder(s): NIH/NIAMS

The long-term goal of these studies is to understand the cellular and molecular mechanisms that control bone development and homeostasis. During the past funding period, significant progress has been made in identifying the multiple roles of vascular endothelial growth factor (VEGF) in skeletal development. These roles include serving as chemotactic factor for vascular invasion into cartilage models of future bones, serving as survival factor for chondrocytes in hypoxic regions, promoting matrix production by osteoblasts and chondrocytes...

Funder(s): NIH/NIAMS

Bone morphogenetic proteins (BMPs) were identified as potent bone forming agents based on their ability to induce de novo bone formation in adult animals and this unique feature of BMP activity has led to use of BMPs as therapeutic agents in bone repair. It has also generated intense interest in defining the role endogenous BMPs play in the skeleton. Removal of individual osteogenic BMPs (BMPs 2, 4, 5, 6, 7) during embryonic development shows that loss of any individual BMP can be compensated for by the other BMPs present. Mice in which...

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...

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

Calcitonin (CT) is the most potent and rapidly acting known inhibitor of bone resorption that targets the osteoclast (OC) directly. CT was the first therapeutic agent used to inhibit excessive bone resorption in osteoporosis and other conditions. It is still used, and new formulations for treating osteoarthritis and osteoporosis are currently in development, despite the fact that a reported loss of efficacy with time has somewhat limited clinical use. Thus, new information about the...

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...

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

Bone resorption is performed by the mature osteoclast. To resorb bone, osteoclasts require both the presence of dynamic actin adhesion structures in the sealing zone (podosomes) and very efficient endocytosis in the ruffled-border domain. Data generated in our laboratory within the last five years has clearly established that two signaling enzyme activities are directly involved in the regulation of both bone resorption and actin dynamics in the osteoclast. On the one hand, we have shown...