Transcription Factors in Bone: Developmental and Pathological Aspects - Engineered Bone: Tissue Engineering Intelligence Unit - page 3

C HAPTER 1

Transcription Factors in Bone:
Developmental and Pathological Aspects

Xiangli Yang and Gerard Karsenty
Many transcription factors involved in bone development have been identified through

studies of human patients with genetic diseases and of genetically modified mice.
Some of them are specific for a particular cell lineage and act as developmental
regulators of cell differentiation. Others are not bone cell-specific but are predominantly ex-
pressed in bone tissues during development and more importantly have a function restricted to
controlling bone cell proliferation or differentiation. The molecular elucidation of mechanisms
governing bone cell differentiation is of particular importance considering the incidence and
severity of the diseases that affect skeletal development and function. In this review, we focus
on the transcription factors that are essential for regulation of cell differentiation during skel-
etal development. In the later part of this review, we will provide examples of transcription factors
affecting patterning of the skeleton and whose functions were uncovered by human genetic
studies.

Bone Development
Bone and cartilage are the two tissues forming skeleton in vertebrates. These two tissues
contain three specific cell types scattered within an extracellular matrix. Osteoblasts or
bone-forming cells and osteoclasts or bone-resorbing cells reside in bone and chondrocytes in
cartilage. The osteoblasts are derived from mesenchymal stem cells and are located on the bony
surfaces. They are responsible for synthesizing matrix proteins that subsequently become min-
eralized, a process called bone formation. Osteoclasts are cells of hematopoietic origin that are
responsible for resorbing extracellular matrix (ECM), a process called bone resorption.
Chondrocytes in cartilage shares the same origin with osteoblasts; they also play important
roles in endochondral ossification (see below).
The earliest forms of skeleton are the primitive mesenchymal condensations that formed
when undifferentiated mesenchymal cells migrate into areas destined to become bone. In mouse,
mesenchymal condensation begins to form at 9.5 days post coitum (dpc). These mesenchymal
condensations can eventually become bone through two distinct processes. During intramem-
branous ossification, cells of mesenchymal condensations differentiate directly into osteoblasts
without any intermediate step. Bones formed through this process include frontal, parietal,
and parts of the temporal and occipital bones, the majority of the facial bones, and the clavicles. 1
All other bones are formed through endochondral ossification, a two-step process. At 11.5 dpc
of mouse embryonic development, cells in the mesenchymal condensation differentiate first
into chondrocytes to create a cartilaginous anlage of the future bone. This process, also called
chontrogenesis, will give rise to essentially an entire skeleton consisting of cartilaginous ele-
ments. In the center of each cartilaginous anlage, cells stop dividing and become hypertrophic
chondrocytes, a subpopulation of chondrocytes surrounded by a calcified ECM. Vascular inva-
sion from this ECM will bring in osteoblast progenitors that will form ossification centers. The