Center of Biomedical Research Excellence (COBRE) for Skeletal Health and Repair

Endocrine and Nutritional Control of Long Bone Growth

Principal Investigator: Chanika Phornphutkul, MD

Abstract

Linear bone growth and maintenance of articular cartilage both require the proliferation and differentiation of chondrocytes. Much of the work done on chondrogenesis has focused on the role of the growth hormone (GH)/insulin-like growth factor-I (IGF-I) axis. While it has long been known that nutrient deprivation impairs linear growth, this has widely been considered to be a function of indirect nutrient effects through modulation of the GH/IGF-I axis. However, preliminary data indicates that the essential amino acid leucine can directly modulate chondrogenesis. Given that chondrocyte differentiation involves cellular hypertrophy, and that the recently characterized mammalian Target of Rapamycin (mTOR) pathway regulates cell size in response to nutrient availability, Chanika Phornphutkul hypothesized that nutrient signaling via mTOR might exert direct effects on chondrocytes.

In preliminary studies, she found that rapamycin, an mTOR inhibitor, blocked differentiation of ATDC5 chondrogenic cells. However, leucine restriction also inhibited differentiation. However, a preliminary examination of the signaling effects of rapamycin versus leucine restriction indicated differences. Similar results in an intact in vivo system, fetal rat metatarsal explants, showed differences between the effects of rapamycin and leucine restriction.

Based on these observations, she is conducting the following aims:
  • Specific Aim 1: She will characterize and compare the induction of chondrocyte differentiation by IGF-I and insulin, focusing on actions mediated through the nutrient-sensing kinase mTOR.
  • Specific Aim 2: She will test the hypothesis that restriction of the availability of essential amino acids has a direct effect on chondrocyte proliferation and differentiation, and that this effect is mediated through effects on mTOR as well as through mTOR-independent mechanisms, which she will characterize.
  • Specific Aim 3: Throughout the course of the studies, the physiological significance of key findings will be assessed through parallel studies using a more physiological model of chondrogenesis and bone growth, fetal rat metatarsal explant cultures. This work has the potential to establish a role for nutrients in the indirect regulation of chondrogenesis via insulin and in direct regulation via the mTOR pathway.

Publications

  1. Phornphutkul, C, Wu KY, Auyeung V, Chen Q, Gruppuso PA. The role of the mTOR nutrient signaling pathway in chondrocyte differentiation. Developmental Dynamics. 2008; 237:702-12.
  2. Sanders JA, Lakhani A, Phornphutkul C, Wu KY, Gruppuso PA. The effect of rapamycin on DNA synthesis in multiple tissues from late gestation fetal rats and postnatal rats. American Journal of Physiology, Cell Physiology. 2008 Aug;295(2):C406-13.
  3. Philips B, Phornphutkul C, Laufgraben M. A Novel Mutation of the Succinate Dehydrogenase D Gene In A Patient With Recurrent Pheochromocytoma And Functional Paraganglioma. The Endocrinologist. October 2008;18:99-101.  
  4. Phornphutkul C, Lee M, Voigt C, Wu K-Y, Ehrlich M, Grupposo PA, Chen Q. The effect of rapamycin on bone growth in rabbits . Journal of Orthopaedic Research.2009 Sep;27(9): 1157-61.
  5. Phornphutkul C, Gruppuso PA. Disorders of the growth plate. Current Opinion in Endocrinology, Diabetes and Obesity 2009, Dec 16(6), 430-4.
  6. Kim MS, Wu KY, Auyeung VA, Chen Q, Gruppuso PA, Phornphutkul C. Leucine restriction inhibits chondrocyte proliferation and differentiation through mechanisms both dependent and independent of mTOR signaling. American Journal of Physiology: Endocrine and Metabolism, 2009 Jun;296(6):E1374-82 .
  7. Woo D, Phornphutkul C, Laptook A. Early and Severe Indirect Hyperbilirubinemia as a Manifestation of Galactosemia,. Journal of Perinatology, 2010 Apr;30(4):295-7.
  8. Peipert J, Rohr F, Johnson D, Phornphutkul C, Waisbren, S. Changes in Metabolic Control of Phenylketonuria in Children Attending a Summer Camp: Pre- and Post- Assessment of a nutritional Intervention. ICAN: Infant, Child, & Adolescent Nutrition Journal. 2010 Apr; 2(2);117-119.
  9. Bourjelly G, Chalhoub M, Alleyne T, McNeilly B, Phornphutkul C, Woodfield C. Effect of a single exposure to iodinated contrast media in utero on neonatal thyroid function. Radiology 2010 Sep;256(3):744-50.
  10. Temu T, Wu KY, Gruppuso PA, Phornphutkul C. Ascorbic acids induced differentiation of ATDC5 cells. American Journal of Physiology. 2010 Aug;299(2):E325-34.
  11. Beck N, Johnston J, Lemke K, Pogacar P, Phornphutkul C. Rhode Island metabolic newborn screening. Medicine and Health Rhode Island. 2010. In press.
  12. Woo HC, Lizarda A, Tucker R, Mitchell M, Vohr B, Oh W, Phornphutkul C. Congenital hypothyroidism with a delayed thyroid stimulating hormone (TSH) elevation in very low birth weight and extremely low birth weight infants: Incidence and growth and developmental outcome. Journal of Pediatrics. 2011, In press.  
Center of Biomedical Research Excellence (COBRE) for Skeletal Health and Repair