Intrauterine Growth Restriction Decreases Endochondral Ossification and Bone Strength in Female Rats

Abstract

Intrauterine growth restriction (IUGR) modifications to postnatal skeletal growth may increase adult fracture, especially in females who have greater risk of osteoporosis. Little is known about the effect of IUGR on the patterns of postnatal endochondral ossification and bone development. Here for the first time we reveal bone formation, mineralization, and strength in IUGR female rats during early postnatal life and adulthood. Endochondral ossification rate of the hypertrophic zone (HZ) and hypertrophic cell length (HCL) at distal femur and proximal tibia, and primary ossification center (POC) of the whole femur and tibia were quantified at birth to day 21. Bone area (BA), bone mineral content (BMC), and bone density by dual-energy X-ray absorptiometry and bone strength determined from three-point bending were measured at days 21 and 120. IUGR femur and tibia HZ, HCL, and POC were significantly diminished at birth to day 21. IUGR decreased BA and BMC as well as femur/tibia diameter, length, stiffness, and peak load values at days 21 and 120. Our findings demonstrate a negative long-term effect of IUGR on bone size, mineral content, and strength in weanling and adult female rats. We speculate that IUGR decreases endochondral ossification responsiveness, and in turn, postnatal linear skeletal growth, mineralization, and strength in female rats.

Keywords

intrauterine growth restriction - endochondral ossification - bone mineralization - bone strength

• References

• 1 Peacock M, Turner CH, Econs MJ, Foroud T. Genetics of osteoporosis. Endocr Rev 2002; 23: 303-326
• 2 Javaid MK, Cooper C. Prenatal and childhood influences on osteoporosis. Best Pract Res Clin Endocrinol Metab 2002; 16: 349-367
• 3 Kinzler WL, Vintzileos AM. Fetal growth restriction: a modern approach. Curr Opin Obstet Gynecol 2008; 20: 125-131
• 4 Cetin I, Alvino G. Intrauterine growth restriction: implications for placental metabolism and transport. A review. Placenta 2009; 30 (Suppl A) S77-S82
• 5 Rosenberg A. The IUGR newborn. Semin Perinatol 2008; 32: 219-224
• 6 Barker DJP. The Wellcome Foundation Lecture, 1994. The fetal origins of adult disease. Proc Biol Sci 1995; 262: 37-43
• 7 Hales CN, Barker DJ. Type 2 (non-insulin-dependent) diabetes mellitus: the thrifty phenotype hypothesis. Diabetologia 1992; 35: 595-601
• 8 Yarbrough DE, Barrett-Connor E, Morton DJ. Birth weight as a predictor of adult bone mass in postmenopausal women: the Rancho Bernardo Study. Osteoporos Int 2000; 11: 626-630
• 9 Düppe H, Cooper C, Gärdsell P, Johnell O. The relationship between childhood growth, bone mass, and muscle strength in male and female adolescents. Calcif Tissue Int 1997; 60: 405-409
• 10 Jones G, Dwyer T. Birth weight, birth length, and bone density in prepubertal children: evidence for an association that may be mediated by genetic factors. Calcif Tissue Int 2000; 67: 304-308
• 11 Yarbrough DE, Barrett-Connor E, Morton DJ. Birth weight as a predictor of adult bone mass in postmenopausal women: the Rancho Bernardo Study. Osteoporos Int 2000; 11: 626-630
• 12 Düppe H, Cooper C, Gärdsell P, Johnell O. The relationship between childhood growth, bone mass, and muscle strength in male and female adolescents. Calcif Tissue Int 1997; 60: 405-409
• 13 Cooper C, Cawley MID, Bhalla A , et al. Childhood growth, physical activity, and peak bone mass in women. J Bone Miner Res 1995; 10: 940-947
• 14 Widdowson EM, McCance RA. The effect of finite periods of undernutrition at different ages on the composition and subsequent development of the rat. Proc R Soc Lond B Biol Sci 1963; 158: 329-342
• 15 Romano T, Wark JD, Owens JA, Wlodek ME. Prenatal growth restriction and postnatal growth restriction followed by accelerated growth independently program reduced bone growth and strength. Bone 2009; 45: 132-141
• 16 Mehta G, Roach HI, Langley-Evans S , et al. Intrauterine exposure to a maternal low protein diet reduces adult bone mass and alters growth plate morphology in rats. Calcif Tissue Int 2002; 71: 493-498
• 17 Nilsson O, Marino R, De Luca F, Phillip M, Baron J. Endocrine regulation of the growth plate. Horm Res 2005; 64: 157-165
• 18 Smink JJ, Gresnigt MG, Hamers N, Koedam JA, Berger R, van Buul-Offers SC. Short-term glucocorticoid treatment of prepubertal mice decreases growth and IGF-I expression in the growth plate. J Endocrinol 2003; 177: 381-388
• 19 Baserga M, Bares AL, Hale MA , et al. Uteroplacental insufficiency affects kidney VEGF expression in a model of IUGR with compensatory glomerular hypertrophy and hypertension. Early Hum Dev 2009; 85: 361-367
• 20 Fu Q, Yu X, Callaway CW, Lane RH, McKnight RA. Epigenetics: intrauterine growth retardation (IUGR) modifies the histone code along the rat hepatic IGF-1 gene. FASEB J 2009; 23: 2438-2449
• 21 Unterman TG, Simmons RA, Glick RP, Ogata ES. Circulating levels of insulin, insulin-like growth factor-I (IGF-I), IGF-II, and IGF-binding proteins in the small for gestational age fetal rat. Endocrinology 1993; 132: 327-336
• 22 World Medical Association; American Physiological Society. Guiding principles for research involving animals and human beings. Am J Physiol Regul Integr Comp Physiol 2002; 283: R281-R283
• 23 Hubscher CH, Brooks DL, Johnson JR. A quantitative method for assessing stages of the rat estrous cycle. Biotech Histochem 2005; 80: 79-87
• 24 Chen H, Miller S, Shaw J, Moyer-Mileur L. Massage therapy during early postnatal life promotes greater lean mass and bone growth, mineralization, and strength in juvenile and young adult rats. J Musculoskelet Neuronal Interact 2009; 9: 278-287
• 25 Chen H, Tian XY, Liu XQ, Setterberg RB, Li M, Jee WSS. Alfacalcidol-stimulated focal bone formation on the cancellous surface and increased bone formation on the periosteal surface of the lumbar vertebrae of adult female rats. Calcif Tissue Int 2008; 82: 127-136
• 26 Turner CH, Burr DB. Basic biomechanical measurements of bone: a tutorial. Bone 1993; 14: 595-608
• 27 Anonymous. Shear and three-point bending test of animal bone. ASAE Standards. ASAE 1992; S459: 417-419
• 28 Cooper C, Eriksson JG, Forsén T, Osmond C, Tuomilehto J, Barker DJP. Maternal height, childhood growth and risk of hip fracture in later life: a longitudinal study. Osteoporos Int 2001; 12: 623-629
• 29 Baker J, Liu JP, Robertson EJ, Efstratiadis A. Role of insulin-like growth factors in embryonic and postnatal growth. Cell 1993; 75: 73-82
• 30 Beltrand J, Alison M, Nicolescu R , et al. Bone mineral content at birth is determined both by birth weight and fetal growth pattern. Pediatr Res 2008; 64: 86-90
• 31 Haley S, O'Grady S, Gulliver K , et al. Mechanical-Tactile Stimulation (MTS) intervention in a neonatal stress model improves long-term outcomes on bone. J Musculoskelet Neuronal Interact 2011; 11: 234-242
• 32 Delany AM, Durant D, Canalis E. Glucocorticoid suppression of IGF I transcription in osteoblasts. Mol Endocrinol 2001; 15: 1781-1789
• 33 Mackie EJ, Ahmed YA, Tatarczuch L, Chen KS, Mirams M. Endochondral ossification: how cartilage is converted into bone in the developing skeleton. Int J Biochem Cell Biol 2008; 40: 46-62
• 34 Radetti G, Renzullo L, Gottardi E, D'Addato G, Messner H. Altered thyroid and adrenal function in children born at term and preterm, small for gestational age. J Clin Endocrinol Metab 2004; 89: 6320-6324