OSTEOBLAST DEVELOPMENT

Role of Runx2-Filamin A interaction in Osteoblast development

Chapter 1: Introduction

1.1 Osteoblasts

Bone-forming cells are called osteoblasts (Sommerfeldt and Rubin 2001), which originate from the mesenchymal stem cells in bone marrow (Ducy et al. 2000). These multipotent mesenchymal stem cells can result in osteoblastic, adipocytic, or chondrocytic lineages (Cohen 2006; Compston 2002) depending on the specific stimuli. The osteoblasts perform various roles, and two of the essential roles include laying down osteoid, which is an extracellular matrix protein, and maintaining the skeletal architecture by supplying various factors that are vital to the differentiation of osteoclasts (Mackie 2003). Osteoblasts are also considered hematopoietic stem cells, because they produce bone marrow (Wilson and Trumpp 2006; Zhu and Emerson 2004; Neiva et al. 2005). To prevent the mesenchymal cells from differentiating into the adipocytic or chondrocytic lineages rather than the osteoblast lineage, the expression of Runt-related transcription factor-2 (RUNX2) is essential. Another transcription factor, osterix (Osx), is essential to carrying out the differentiation of the pre-osteoblast into a mature osteoblast after which point it is governed mostly by Type I collagen and alkaline phosphatase (ALP) for its differentiation.

1.2 Bone Cells

When cells are exposed to mechanical stimuli, biochemical signals are transduced

through the cells that determine how they will respond. This process is referred to as

mechanotransduction. The mechano transduction pathways may initiate extra cellular

signaling mechanisms that will inform other cells about the mechanical environment.

Intracellular signaling may also be initiated along pathways to the nucleus where

osteogenic genes can be expressed. All of the biochemical responses are integrated to

determine how the cells will remodel bone tissue and adapt the mechanical properties of

the bone to the habitual loads.

1.3 Bone Remodeling

An elegant example of how cells are able to modify the mechanical properties of

the surrounding tissue can be found in bone. In healthy individuals, bone tissue is

continually being remodeled by removing existing tissue and replacing it with newly

formed bone. At any instant, approximately 20% of cortical bone and 10% of trabecular

surfaces are undergoing this remodeling process. Constantly replacing the bone

tissue enables damaged regions of the bone to be repaired. Furthermore, it provides

the opportunity for bone cells to adjust the mechanical properties of the bone so they are

appropriate for the loads that are applied to it. During periods of inactivity,

such as prolonged bed rest or space travel , the forces experienced by the bones of the lower extremities are reduced, and the bone cells respond by removing more bone tissue than is replaced, As a result, the apparent stiffness of these bones decreases.

Bone is a porous tissue that contains a significant volume of interstitial fluid.

Loading the bone causes this fluid to perfuse through the tissue and the shear stress generated by this fluid movement may be detected by the bone cells.

1.3 Runt-related Transcription Factor 2 (RUNX2)

The RUNX2 gene is present on chromosome number 6 (Blyth et al. 2001), and contains eight exons. The product of the gene is a protein consisting of a sequence with 513 amino acids. The Runt domain of this protein starts from amino acid number ...