Scientists Discover Protein that Stimulates Bone Growth in Humans

U.S. scientists have discovered that a protein called Jagged-1 stimulates stem cells to differentiate into bone-producing cells.

Structure of the Jagged 1 protein and the location of the JAG1 gene on the short arm of chromosome 20

The findings, accepted for publication in the journal Stem Cells, suggest Jagged-1 could help both human and animal patients heal from bone fractures faster and may form the basis of treatments for a rare metabolic condition called Alagille syndrome.

Although human bones seem static and permanent, bone tissue actually forms and reforms throughout our lives. Cells called osteoblasts form bone and are derived from precursor cells known as mesenchymal stem cells, which are stored in bone marrow. These stem cells must receive specific signals from the body in order to become osteoblasts.

Prior research had identified a molecule called bone morphogenic protein (BMP), as one of these proteins that drives stem cells to become bone-forming cells. As a result, BMP has been used clinically to help patients healing from broken bones or to perform spinal fusions without relying on patients’ own bone tissue.

“But it has become clear that BMPs have some issues with safety and efficacy. In the field we’re always searching for new ways for progenitor cells to become osteoblasts so we became interested in the Notch signaling pathway,” said senior author Prof Kurt Hankenson of the University of Pennsylvania’s School of Veterinary Medicine.

This molecular signaling pathway is found in most animal species and is known to play a role in stem cell differentiation. The researchers chose to investigate one of the proteins that acts in this pathway by binding to the Notch receptor, Jagged-1. The team has previously shown that Jagged-1 is highly expressed in bone-forming cells during fracture healing and that introducing Jagged-1 to mouse stem cells blocked the progression of stem cells to osteoblasts.

“That had been our operating dogma for a year or two,” Prof Hankenson said.

Next the researchers decided to see what happened when Jagged-1 was introduced to human stem cells. There they came upon a very different result.

“It was remarkable to find that just putting the cells onto the Jagged-1 ligand seemed sufficient for driving the formation of bone-producing cells,” he said.

This finding aligns with other evidence linking Jagged-1 to bone formation. Patients with a rare disease known as Alagille syndrome frequently have mutations in the gene that codes for Jagged-1. Individuals with this condition have problems with their metabolism that severely affect their livers but also tend to have challenges with their skeletal system and break bones easily.

Furthermore, genome-wide association studies, which search large populations for mutations that may be linked with particular characteristics, have found a connection between mutations near the Jagged-1 gene and low bone mass.

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Bibliographic information: Fengchang Zhu et al. 2013. Pkcδ Is Required for Jagged-1 Induction of hMSC Osteogenic Differentiation. Stem Cells, accepted for publication; doi: 10.1002/stem.1353