Changes in dietary protein may override inherited skeletal abnormalities
Eating a diet with either high or low amounts of protein may override certain inherited developmental malformations of the skeleton, according to a new report in the December issue of the journal Cell Metabolism, published by Cell Press. Such so-called skeletal dysplasiae include more than 200 disorders of bone growth that lead to skeletal disproportions.
A study of mice led by Gerard Karsenty of Columbia University now uncovers new details of the molecular machinery that governs bone formation. Specifically, the researchers found that loss of a gene that is mutated in patients with a condition called neurofibromatosis (NF) type I causes an abnormal increase in activity of genes responsible for manufacturing bone.
The researchers also found a more general link between dietary amino acids—the building blocks of proteins—and normal bone development. That result raised the possibility that changes in nutrition may, in some cases, offer a simple treatment for skeletal dysplasiae, according to the researchers, who conducted the work primarily at Baylor College of Medicine.
“These results not only provide a molecular basis for NF skeletal manifestations,” Karsenty said, “but also identify a hitherto unanticipated connection between amino acid intake and skeletal development.”
Neurofibromatosis type I, a disease which affects an estimated 1 in 3000 to 4000 people in the United States, is caused by loss of function of a gene encoding neurofibromin (NF1). In addition to well-described tumors of the nervous system, the condition in patients often includes skeletal abnormalities that have not been well understood, the researchers said.
“As a result of the paucity of molecular knowledge of how neurofibromin affects bone biology, the only available treatment for these often debilitating manifestations remains surgery,” Karsenty said.
To further elucidate NF1’s skeletal role, Karsenty’s team generated mice that lacked the gene only in bone-building cells called osteoblasts. Examination of these mutant mice found that the transcription factor known as ATF4 plays a crucial role in mediating neurofibromin signaling. ATF4 is known to control the activity of other genes that enhance bone formation through amino acid import and collagen synthesis in osteoblasts. Collagen is a fibrous protein and an important structural component of bone.
ATF4-dependent collagen synthesis and bone formation increased in mice lacking neurofibromin in osteoblasts, the researchers reported. In keeping with ATF4’s function in amino acid transport, they found that the abnormalities observed in NF1-deficient mice could be reversed with a low-protein diet. A low-protein diet fed to mutant mice from birth to 4 months of age normalized bone formation and bone mass without affecting the weight of other organs, the researchers found.
The remarkable efficacy of a low-protein diet in rescuing skeletal manifestations of a disease caused by increase in ATF4 activity suggested to the researchers that a high-protein diet might similarly reverse skeletal syndromes characterized by a decrease in ATF4 function.
Indeed, the researchers found that mice deficient for ATF4 or another gene in the ATF4 pathway who received a diet enriched in protein before and after birth overcame low bone mass and other developmental defects.
By showing that skeletal dysplasiae linked to the gene ATF4 are treatable by dietary manipulations, the study reveals a molecular connection between nutrition and skeletal development, the researchers concluded. “More generally, our results illustrate how the precise knowledge of the molecular mechanism of action of a given gene involved in the pathogenesis of a human genetic disease can potentially translate into therapeutic interventions,” they said.
The researchers include Florent Elefteriou of Baylor College of Medicine in Houston, TX, University of Texas Health Science Center at San Antonio, TX, and Vanderbilt University Medical Center in Nashville, TN; Douglas Benson and Luis F. Parada of University of Texas Southwestern Medical Center in Dallas, TX; Hideaki Sowa of Baylor College of Medicine in Houston, TX and Columbia University in New York; Michael Starbuck and Xiuyun Liu of Baylor College of Medicine in Houston, TX; David Ron of New York University School of Medicine in New York; Gerard Karsenty of Baylor College of Medicine in Houston, TX, University of Texas Health Science Center at San Antonio, TX, and Columbia University in New York.
This work was supported by grants from National Institutes of Health (G.K. and L.P.); The Children’s Tumor Foundation (F.E.); the Japan Osteoporosis Foundation, The Uehara Memorial Foundation, Kanzawa Medical Research Foundation, and The Mochida Memorial Foundation for Medical and Pharmaceutical Research (H.S.).
Elefteriou et al.: “ATF4 mediation of NF1 functions in osteoblast reveals a nutritional basis for congenital skeletal dysplasiae.” Publishing in Cell Metabolism 4, 441–451, December 2006 DOI 10.1016/j.cmet.2006.10.010 www.cellmetabolism.org
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