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Catch-Up Growth after Hypothyroidism Is Caused by Delayed Growth Plate Senescence

Developmental Endocrinology Branch (R.M., A.H., K.M.B., L.S., J.A.E., O.N., J.B.), National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892; Pediatric Endocrinology Unit (R.M.), The Massachusetts General Hospital for Children, Boston, Boston, Massachusetts 02114; Department of Pediatrics (J.A.E.), Leiden University Medical Center, 2300 RC Leiden, The Netherlands; Center for Molecular Medicine and Pediatric Endocrinology Unit (O.N.), Department of Woman and Child Health, Karolinska Institutet and Karolinska University Hospital, SE-171 76 Stockholm, Sweden

Address all correspondence and requests for reprints to: Jeffrey Baron, M.D., National Institutes of Health, National Institute of Child Health and Human Development, Building CRC, Room 1-3330, 10 Center Drive MSC 1103, Bethesda, Maryland 20892-1103. E-mail: jeffrey.baron{at}nih.gov.

Catch-up growth is defined as a linear growth rate greater than expected for age after a period of growth inhibition. We hypothesized that catch-up growth occurs because growth-inhibiting conditions conserve the limited proliferative capacity of growth plate chondrocytes, thus slowing the normal process of growth plate senescence. When the growth-inhibiting condition resolves, the growth plates are less senescent and therefore grow more rapidly than normal for age. To test this hypothesis, we administered propylthiouracil to newborn rats for 8 wk to induce hypothyroidism and then stopped the propylthiouracil to allow catch-up growth. In untreated controls, the growth plates underwent progressive, senescent changes in multiple functional and structural characteristics. We also identified genes that showed large changes in mRNA expression in growth plate and used these changes as molecular markers of senescence. In treated animals, after stopping propylthiouracil, these functional, structural, and molecular senescent changes were delayed, compared with controls. This delayed senescence included a delayed decline in longitudinal growth rate, resulting in catch-up growth. The findings demonstrate that growth inhibition due to hypothyroidism slows the developmental program of growth plate senescence, including the normal decline in the rate of longitudinal bone growth, thus accounting for catch-up growth.

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