Title: Osteoblast regulators

Bone morphogenic proteins (BMPs)

BMPs are a group of cytokines and growth factors that induce bone and cartilage formation. They are secreted by osteoblasts and osteocytes. Until now, ca. 50 BMPs have been identified, several of them important for skeletal development and function.

Among the high number of BMPs, the most important ones acting on osteoblasts differentiation are BMP-2 and BMP-7. Both are used as stimulator of bone formation in clinical applications.

BMPs bind to specific receptors on the cell surface. Intracellular signal transduction involves smad.

BMP or BMP receptor mutations can cause a number of pathologies, among them myositis ossificans, craniosynostosis, pulmonary hypertension, brachydactyly and hand malformations.

Runx2

Runt related transcription factor 2 (Runx2), also called Cbfa1, is a key transcription factor involved in the regulation of osteoblast differentiation. Runx induces the differentiation of mesenchymal stem cells in direction of osteoblasts and chondroblasts and inhibits the differentiation into adipocytes and myocytes.

Mutations in the Runx2 are associated with cleidocranial dysostosis. Symptoms of this autosomal dominant disease are partly or completely missing collarbones (-> hypermotility of shoulders), failure of fontanel closure, disturbed dentition and short stature.

Osterix

Osterix is a transcription factor acting downstream of Runx2. It regulates the differentiation of preosteoblasts in the osteoblast direction and inhibits differentiation into chondroblasts. Production of osterix is depenent on Runx2.

Wnt

Wnt is a signaling molecule secreted by osteoblasts. Its name is composed from the Drosophila gene wingless + mouse gene int. There are a number of different Wnt proteins

Wnt binds to a receptor on the cell membrane called frizzled. This receptor forms a complex with LRP-5, a transmembrane protein. This complex leads via several steps to an increase in the transcription factor β-catenin that triggers transcription of several genes for matrix proteins (e.g. OPG).

Wnt acts in positive feedback loop with BMPs.

Wnt play an important role in the polarization of the embryo, limb patterning and skeletal development.

An animated course on Wnt signaling can be found at the following website:
http://courses.washington.edu/bonephys/physwnt.html