Osteoblasts, the cells that form bone, are mesenchymal in origin and like other mesenchymal lineages arise from pluripotential stem cells through a series of developmental transitions. The osteoblast developmental pathway is only partially understood, particularly in its early stages, where little is know about the cell fate decisions that lead to commitment to the osteoblast lineage. Adipocytes, the cells that produce fat, likely share a common early progenitor with osteoblasts, although little is known about the molecular control of this lineage bifurcation. Growing evidence indicates that transcription factors required for B lymphocyte development from hematopoietic stem cells are critical for proper skeletal development although as yet none have been implicated in osteoblast differentiation. We have discovered that Early B Cell Factor-1 (EBF-1), a transcription factor essential for B cell development, is expressed in osteoblasts and plays a critical role in controlling osteoblast development. EBF-1 deficient mice are runted, have increased bone formation parameters, and display a striking increase in numbers of osteoblasts. Remarkably, these mice also exhibit a dramatic expansion of adipocytes in the medullary canal of long bones. The central hypothesis underlying this proposal is that EBF-1 and its upstream regulatory and downstream target genes are critical for the control of osteoblast and adipocyte development. Our findings suggest that EBF-1 and EBF-1 deficient mice provide a unique opportunity to gain significant molecular insight into the development of these two lineages. The long-term goal of our work is to identify the mechanism(s) by which EBF-1 regulates osteogenesis and adipogenesis. The first step in achieving this goal is a careful analysis of the EBF-1 deficient mice at the histological, morphological, cellular, and molecular level, which will provide the information needed to formulate detailed molecular hypotheses for the role of EBF-1 in bone and fat cell development. Toward this end, we will pursue two Specific Aims: 1) To determine the bone phenotype of EBF-1 deficient mice; and 2) To characterize through a quantitative analysis the functional and molecular properties of EBF-1 deficient osteoblasts, osteoblast precursors, and adipocytes. We anticipate that these experiments will lead to new models for osteoblast development and hence for the potential to discover new anabolic pathways. Such information would be applicable to a wide variety of skeletal defects including age-related osteopenia, post-menopausal osteoporosis, fracture repair, and extended survival of prosthetic implants. ? ? ?
| Gao, Hui; Mejhert, Niklas; Fretz, Jackie A et al. (2014) Early B cell factor 1 regulates adipocyte morphology and lipolysis in white adipose tissue. Cell Metab 19:981-92 |
| Fretz, Jackie A; Nelson, Tracy; Velazquez, Heino et al. (2014) Early B-cell factor 1 is an essential transcription factor for postnatal glomerular maturation. Kidney Int 85:1091-102 |
| Festa, Eric; Fretz, Jackie; Berry, Ryan et al. (2011) Adipocyte lineage cells contribute to the skin stem cell niche to drive hair cycling. Cell 146:761-71 |
| 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 |
| Fretz, Jackie A; Nelson, Tracy; Xi, Yougen et al. (2010) Altered metabolism and lipodystrophy in the early B-cell factor 1-deficient mouse. Endocrinology 151:1611-21 |
| Horowitz, Mark C; Fretz, Jackie A; Lorenzo, Joseph A (2010) How B cells influence bone biology in health and disease. Bone 47:472-9 |
| Hesslein, David G T; Fretz, Jackie A; Xi, Yougen et al. (2009) Ebf1-dependent control of the osteoblast and adipocyte lineages. Bone 44:537-46 |
| Lorenzo, Joseph; Horowitz, Mark; Choi, Yongwon (2008) Osteoimmunology: interactions of the bone and immune system. Endocr Rev 29:403-40 |
