REGULATION OF BONE REMODELING BY MEGAKARYOCYTES

Yale University, New Haven CT

Investigators

Linked publications & trials

Abstract

DESCRIPTION (Adapted from the Investigator's Abstract): Bone marrow is the source of osteogenic, hematopoietic, and immune cells. The close juxtaposition of these cells makes the bone marrow the focus for many of the regulatory interactions required for homeostatic development of bone. Recent data indicate that hematopoietic cells can influence the differentiation of osteogenic cells. It has been suggested that one such cell, the megakaryocyte, is unique by being the only cell, other than osteoblasts and odontoblasts, to express the matrix proteins osteocalcin and bone sialoprotein. The Principal Investigator has begun an analysis of chimeric mice deficient in either GATA-1 or NF-E2, transcription factors involved in the differentiation of megakaryocytes. These animals experience a developmental block in megakaryocyte differentiation resulting in a phenotype characteristic by greately-increased numbers of megakaryocytes in the spleen and bone marrow with concomitant drastic reduction or total absence of mature platelets. Preliminary data indicate these mice also develop strikingly increased trabecular and cortical bone mass, with increased bone formation, increased numbers of osteoblasts and normal numbers of osteoclasts. It is hypothesized that the megakaryocytes are the causative agent of the increased bone formation in these mice. Four specific aims will be pursued: 1) Quantitative analysis of the bone phenotype in GATA-1 knockdown and NF-E2 knockout mice; 2) Quantitative functional analysis of mutant and control osteoblasts in vitro; 3) Quantitative functional analysis of mutant and control megakaryocytes in vitro; and 4) Functional analysis of the megakaryocyte-osteoblast interaction. The long-term goal of this proposal is to identify the mechanism(s) by which the megakaryocytes induce the marked increase in bone formation. These studies will show how megakaryocytes regulate osteoblast differentiation or function and further identify the interactions between hematopoietic and osteogenic cells. It is well established that once the skeleton starts to lose bone, whether from age, menopause, or other causes, it is difficult, if not impossible, to build bone mass. No anabolic agent is available which adds significant amounts of new bone to the skeleton. Therefore, new models of bone formation present the potential to discover new unrecognized anabolic pathways. This is particularly true for in vivo models with an established bone phenotype. Such information would be applicable to a wide variety of skeletal defects including post-menopausal osteoporosis, age-related osteopenia, fracture repair, and extended survival of prosthetic implants.