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. A growing body of evidence suggests that megakaryocytes (MK) or their secreted factors play a role in skeletal homeostasis. During the current granting period we began our analysis of chimeric mice deficient in either GATA-1 or NF-E2, transcription factors required for the differentiation of MK. These animals have a developmental block in MK differentiation resulting in a phenotype characterized by markedly increased numbers of MK in the bone marrow and spleen with a concomitant drastic reduction or total absence of mature platelets. These mice also develop strikingly increased trabecular and cortical bone mass, with increased bone formation, increased numbers of osteoblasts (OB) and increased numbers of osteoclasts (OC). In addition to this novel anabolic effect, which is mediated by cell-cell contact, we have discovered that MK secrete a potent inhibitor(s) of OC differentiation. It is our hypothesis that MK are anabolic for bone. They carry out the dual function of stimulating OB proliferation and inhibiting OC differentiation. Three new Specific Aims will be pursued: 1) a. Determine whether the stage of MK differentiation is important in MK induced OB proliferation; and b. Whether the stage of MK differentiation is important in MK induced inhibition of OC formation: 2) Identification and quantitative functional analysis of the MK soluble factor(s) responsible for the inhibition of OC formation; 3) Identification and quantitative functional analysis of the cell surface associated molecule responsible for OB proliferation. The long-term goal of this proposal is to identity the mechanism(s) by which the MK regulates bone formation. It is well established that once the skeleton starts to lose bone, whether from age, menopause, or other causes, it is difficult to put back bone into the skeleton. This process can be slowed using anti-resorptives. However, few anabolic agent are available that add 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 because they preclude any possibility of in vitro artifacts. 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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR047342-06
Application #
7035794
Study Section
Skeletal Biology Development and Disease Study Section (SBDD)
Program Officer
Sharrock, William J
Project Start
2001-04-01
Project End
2010-01-31
Budget Start
2006-02-01
Budget End
2007-01-31
Support Year
6
Fiscal Year
2006
Total Cost
$351,247
Indirect Cost
Name
Yale University
Department
Orthopedics
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Meijome, Tomas E; Hooker, R Adam; Cheng, Ying-Hua et al. (2015) GATA-1 deficiency rescues trabecular but not cortical bone in OPG deficient mice. J Cell Physiol 230:783-90
Kacena, Melissa A; Gundberg, Caren M; Kacena 3rd, William J et al. (2013) The effects of GATA-1 and NF-E2 deficiency on bone biomechanical, biochemical, and mineral properties. J Cell Physiol 228:1594-600
de Paula, Francisco J A; Horowitz, Mark C; Rosen, Clifford J (2010) Novel insights into the relationship between diabetes and osteoporosis. Diabetes Metab Res Rev 26:622-30
Lemieux, Justin M; Horowitz, Mark C; Kacena, Melissa A (2010) Involvement of integrins alpha(3)beta(1) and alpha(5)beta(1) and glycoprotein IIb in megakaryocyte-induced osteoblast proliferation. J Cell Biochem 109:927-32
Horowitz, Mark C; Fretz, Jackie A; Lorenzo, Joseph A (2010) How B cells influence bone biology in health and disease. Bone 47:472-9
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Lorenzo, Joseph; Horowitz, Mark; Choi, Yongwon (2008) Osteoimmunology: interactions of the bone and immune system. Endocr Rev 29:403-40
Horowitz, Mark C; Lorenzo, Joseph A (2007) B lymphocytes and the skeleton. Ann N Y Acad Sci 1117:82-93

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