Research projects in our lab build on Dr. Conover's discovery of the pregnancy-associated plasma protein A (PAPP-A) in 1974, and more recently on our development of a PAPP-A knockout mouse model. Our work shows that beyond pregnancy, PAPP-A also plays a critical role in amplifying local IGF action during fetal development, vascular injury, bone formation and aging.
Our research projects include:
- Novel anabolic therapy for osteoporosis using IGFs
- PAPP-A and aging
- PAPP-A as a serum marker for acute coronary syndromes
- Role of PAPP-A in atherosclerosis
- Role of PAPP-A in skeletal development and remodeling
Novel anabolic therapy for osteoporosis using IGFs
The ability to stimulate new bone formation and increase bone mass in patients with osteoporosis is an important goal. Patients with a rare syndrome of hepatitis C-associated osteosclerosis (HCAO), who develop marked increases in bone mass as adults, first provided clues for an innovative approach using the IGF system.
The IGFs are important skeletal growth factors, and our detailed analysis of the IGF system in patients with HCAO indicated a unique increase in an IGF-II precursor molecule and IGFBP-2. Subsequent studies in cultured human bones demonstrated preferential binding of the IGF-II/IGFBP-2 complex to bone matrix and stimulation of osteoblast proliferation. Animal studies showed increases in bone mineral density following short-term IGF-II/IGFBP-2 administration. This project is continuing with the preclinical analyses of this novel anabolic approach to the treatment of osteoporosis.
PAPP-A and aging
Diverse species with specific mutations in IGF signal transduction have enhanced resistance to oxidative stress and extended life spans. Our overall hypothesis is that the aging process can be regulated by PAPP-A, which degrades inhibitory IGFBP-4, thereby increasing IGF-I bioavailability. The corollary is that PAPP-A-deficiency, by decreasing IGF availability and receptor signaling, would result in increased longevity.
Our preliminary data indicate that PAPP-A knockout mice live 30 percent to 40 percent longer than do their wild-type littermates.
In this project, we are determining the physiological mechanisms underlying the life span extension in PAPP-A knockout mice by critically assessing the contribution of prenatal programming, metabolism, resistance to oxidative stress, preservation of immune competence and prevention of tumor growth. We have the models and the technology to enable us to make significant contributions to the understanding of PAPP-A and the IGF system in the fundamental biology of aging, with implications for novel strategies to slow the aging process and enhance longevity.
PAPP-A as a serum marker for acute coronary syndromes
Circulating PAPP-A levels are significantly elevated in patients with unstable angina and myocardial infarction, suggesting PAPP-A as a new candidate marker for acute coronary syndromes. We are continuing to evaluate this research.
Role of PAPP-A in atherosclerosis
Using specific monoclonal antibodies, we identified abundant staining for PAPP-A in eroded and ruptured plaques from human arterial specimens. The most intense staining for PAPP-A was at the inflammatory shoulder of the ruptured plaques containing smooth muscle cells and activated macrophages. There was little or no staining for PAPP-A in stable plaques.
Our overall hypothesis is that PAPP-A is a key regulatory factor in the vascular response to injury leading to atherosclerosis and promoting plaque vulnerability.
Experiments are underway to determine the underlying mechanisms for elevated PAPP-A in vulnerable plaque using human tissue and cell models. In addition, we are determining the effect of PAPP-A deficiency and of targeted PAPP-A overexpression on the development and progression of atherosclerotic plaque in mice on an apolipoprotein E-null background.
This project seeks to gain a better understanding of PAPP-A and the IGF system in the fundamental biology of cardiovascular disease and should establish PAPP-A as a therapeutic target in atherosclerosis.
Role of PAPP-A in skeletal development and remodeling
The IGFs are important for the structure and function of the skeleton through their potent anabolic effects on bone cell proliferation, differentiation, survival and matrix protein synthesis.
Using the PAPP-A knockout mouse model and well-characterized mouse and human bone cell cultures, we are testing the central hypothesis that PAPP-A, through its regulation of local IGF bioavailability, is a key regulator of bone formation.
This work includes dynamic and static bone histomorphometry, bone mineral density measurements, mechanical strength testing and gene-expression studies. The information is expected to provide new insights into the physiology and pathophysiology of the IGF system in bone that could lead to novel approaches for treatment of disorders of bone formation.