The Story Behind a Potential Protein Treatment for Achondroplasia

Injecting sFGFR3 induces bone growth in wildtype mice (WT) and achondroplastic mice (Fgfr3ach/+). Adapted from Fig. 2 (1).
Injecting sFGFR3 induces bone growth in wildtype mice (WT) and achondroplastic mice (Fgfr3 ach/+). Adapted from Fig. 2 (1).

Earlier this week, several news outlets reported on a decoy protein as a potential treatment for achondroplasia or, more commonly, dwarfism, but made no mention of its origins.

From the New York Times:

Injections of a decoy protein can restore normal bone growth in mice with dwarfism characteristics, according to a new study, suggesting a possible treatment for humans with the condition.

People born with achondroplasia, the most common form of dwarfism, tend to be short in stature with short arms and legs and a relatively larger head, sometimes resulting in problems with the spine and with hearing and breathing. The condition is caused by a single mutation in the gene Fgfr3, which provides instructions for making a protein involved in the development of bone and brain tissue.

The Fgfr3 gene codes for fibroblast growth factor receptor 3 (FGFR3), a protein found on the surface of cells that in essence serves as an antenna that cells use to communicate with each other.  During normal bone development, cells need to coordinate when to start or to stop making bone. They accomplish this by sending each other messages in the form of signaling proteins. Fibroblast growth factors are one group of proteins that provide cells the cue to stop making bone. When fibroblast growth factors attach to FGFR3, this cue is relayed to the cell. Certain mutations in FGFR3, however, cause the “antenna” to go haywire and transmit that signal for longer than usual resulting in the reduced bone growth typical of achondroplasia.

fgfr3-diagram
The FGFR3 protein is composed of three parts: an extracellular domain that binds to FGFs, a transmembrane (TM) domain that anchors the receptor to the surface of the cell, and an intracellular domain that is responsible for relaying the signal intracellularly. The decoy protein sFGFR3 is secreted because it is missing the transmembrane (TM) domain that anchors it to the cell membrane. Adapted from Fig. 1 (1).

Interestingly, the decoy protein that was injected into the achondroplastic mice is in actuality just a shortened form of FGFR3 called sFGFR3. Normal FGFR3 protein has three parts: a portion that juts out of the cell that acts as the “antenna” for fibroblast growth factor signals called the extracellular domain, an anchor that keeps FGFR3 attached to the cell surface called a transmembrane domain, and a region that is responsible for relaying the signal into the cell called the intracellular domain. In contrast, the sFGFR3 decoy protein is missing the transmembrane domain and has no way of anchoring itself to the cell surface. But since it still has the extracellular portion, sFGFR3 can bind fibroblast growth factors before they reach the mutated FGFR3 proteins. By intercepting the signal, the decoy protein prevents the mutated FGFR3 protein from transmitting instructions to stop making bone. Not only did this strategy restore bone growth in the mice with dwarfism, but it improved other complications associated skeletal abnormalities such as “paraplegia, mortality, and respiratory failure.” The same NYT article was quick to note:

“So yes, they would be taller” with genetic treatment, Dr. Gouze continued, “but that’s not the most important thing.”

One of the more compelling aspects of the decoy protein’s story, though, is that it actually began 12 years ago when a group of researchers from Japan discovered an alternative form of the RNA transcript for the FGFR3 protein being made in skin cancer cells (2). Many genes are transcribed into RNA molecules containing extra sequences, called introns, that aren’t represented in the protein. Before RNA is translated into proteins, the cell machinery will remove these introns and splice together the RNA segments that do code for parts of the protein, called exons. This process is analogous to how movie film is spliced together during editing. Sometimes the machinery is directed to skip certain exons which produces different forms of a protein (think theatrical release versus a director’s cut). In the case of sFGFR3, the RNA segment responsible for the anchor region was skipped.

The Japanese researchers suggested that cells might normally make sFGFR3 as a way to intercept fibroblast growth factors and regulate communication between cells.  Cancer cells, however, behave very differently from normal cells, so it’s hard to tell whether making sFGFR3 is a funky thing that these cancer cells do. Notably, an independent group of UK researchers later found the same alternative RNA transcript for sFGFR3 being made in cells that line the urinary tract, adding weight to the Japanese group’s proposal (3).

While sFGFR3 represents an potential treatment for achondroplasia and its complications, its origin highlights how science progresses by building on previous research. The fact that its story began in cancer cell research just illustrates how you can’t exactly predict where discoveries will eventually lead us.

Related Reading:

Condemned to a Skeletal Prison

References
1. Garcia S., Dirat B., Tognacci T., Rochet N., Mouska X., Bonnafous S., Patouraux S., Tran A., Gual P. & Le Marchand-Brustel Y. & (2013). Postnatal Soluble FGFR3 Therapy Rescues Achondroplasia Symptoms and Restores Bone Growth in Mice, Science Translational Medicine, 5 (203) 203ra124-203ra124. DOI:

2. Terada M., Shimizu A., Sato N., Miyakaze S.I., Katayama H. & Kurokawa-Seo M. (2001). Fibroblast Growth Factor Receptor 3 Lacking the Ig IIIb and Transmembrane Domains Secreted from Human Squamous Cell Carcinoma DJM-1 Binds to FGFs, Molecular Cell Biology Research Communications, 4 (6) 365-373. DOI:

3. Tomlinson D.C. (2005). Alternative Splicing of Fibroblast Growth Factor Receptor 3 Produces a Secreted Isoform That Inhibits Fibroblast Growth Factor-Induced Proliferation and Is Repressed in Urothelial Carcinoma Cell Lines, Cancer Research, 65 (22) 10441-10449. DOI:

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