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The role of estrogen in growth plate chondrogenesis

thesis
posted on 2024-09-03, 01:09 authored by Ola Nilsson

Overall body proportion is determined by the size of the skeleton, which in turn is determined by the rate and duration of longitudinal bone growth. Longitudinal bone growth occurs at the growth plate and is regulated by a variety of hormones and growth factors. During puberty, estrogen contributes to the pubertal growth spurt via an augumentation of the somatotropic axis. Estrogen also advances growth plate senescence and epiphyseal fusion. This effect may be mediated through a direct effect on the stem-like cells of the growth plate. Estrogen is thus involved in the regulation of the rate as well as the duration of longitudinal bone growth. We first studied the localization of the stem-like cells of the growth plate. When the growth plate was removed, re-implantion of resting zone cartilage was sufficient to regenerate a complete growth plate, indicating that the resting zone chondrocytes are the stem-like cells of the growth plate. It was further noted that resting cartilage implanted ectopically alongside the proliferative columns was able to induce a 90-degree shift in the spatial orientation of the proliferative columns. This observation suggests that the resting zone cartilage, by the production of a morphogen, is responsible for the alignment of newly formed proliferative chondrocytes into columns. The identity of the morphogen is unknown but Indian hedgehog and parathyroid hormone-related protein, both important parts of an internal negative feed-back loop for the regulation of proliferation and differentiation of growth plate chondrocytes, are two possible candidates. The expression of these proteins was studied in human growth plate samples collected from pubertal patients undergoing epiphyseal surgery. The expression was predominantly localized to the hypertrophic zone. Thus, neither of these proteins are likely candidates. However, our finding shows that these polypeptides are down regulated during pubertal development. These results suggest that the feedback loop is active in humans, that it may be functional during postnatal bone growth, and that down-regulation of this loop might be important for epiphyseal fusion. To further study the mechanisms for estrogen induced growth plate fusion, we chose to study the developmental pattern of estrogen receptor-alpha (ERalpha) and -beta (ERbeta), in growth plates from rat, a species that does not fuse most of their growth plates during sexual maturation, and in the rabbit, which fuses all of their growth plates during sexual maturation. We found that ERalpha and -beta are expressed throughout development and that the pattern of expression is well conserved between the two species. The expression of estrogen receptors prior to sexual maturation provides an explanation for estrogen responsiveness in early postnatal life, seen, for example, in children with precocious puberty. Therefore, the lack of estrogen action on the growth plate in early life is due to lack of ligand, not lack of receptor. We also localized the expression of ERalpha, ERbeta, and androgen receptor protein in the human epiphyseal growth plate and determined whether the expression patterns vary between different stages of puberty. The finding that ERalpha, ERbeta, and androgen receptor are expressed in all zones of the growth plate supports a direct effect of sex steroids on the human growth plate and may explain many of the effects of sex steroids on growth plate cartilage, including the effects on proliferation, growth rate, senescence, and epiphyseal fusion. Selective estrogen receptor modulators might be useful tools for modulation of pubertal growth. Therefore, we elucidated the effects of raloxifene on the growth plate. Our findings show that raloxifene acts as an estrogen receptor agonist on the growth plate without affecting the uterus. It may therefore provide an alternative clinical treatment to induce growth plate fusion while avoiding possible risks associated with estrogen action on endometrium and breast tissue.

List of scientific papers

I. Abad V, Meyers JL, Weise M, Gafni RI, Barnes KM, Nilsson O, Bacher JD, Baron J. (2002). The role of the resting zone in growth plate chondrogenesis. Endocrinology. 143(5):1851-7.
https://pubmed.ncbi.nlm.nih.gov/11956168

II. Kindblom JM, Nilsson O, Hurme T, Ohlsson C, Savendahl L. (2002). Expression and localization of Indian hedgehog (Ihh) and parathyroid hormone related protein (PTHrP) in the human growth plate during pubertal development. J Endocrinol. 174(2):R1-6.
https://pubmed.ncbi.nlm.nih.gov/12176676

III. Nilsson O, Abad V, Chrysis D, Ritzen EM, Savendahl L, Baron J. (2002). Estrogen receptor-alpha and -beta are expressed throughout postnatal development in the rat and rabbit growth plate. J Endocrinol. 173(3):407-14.
https://pubmed.ncbi.nlm.nih.gov/12065230

IV. Nilsson LO, Boman A, Savendahl L, Grigelioniene G, Ohlsson C, Ritzen EM, Wroblewski J. (1999). Demonstration of estrogen receptor-beta immunoreactivity in human growth plate cartilage. J Clin Endocrinol Metab. 84(1):370-3.
https://pubmed.ncbi.nlm.nih.gov/9920110

V. Nilsson O, Chrysis D, Pajulo O, Boman A, Holst M, Rubinstein J, Ritzen EM, Savendahl L. (2002). Localization of estrogen receptor-alpha, -beta and androgen receptor in the human growth plate at different pubertal stages. [Submitted]

VI. Nilsson O, Falk J, Ritzen EM, Baron J, Savendahl L. (2002). Raloxifene acts as an estrogen agonist on the rabbit growth plate. [Submitted]

History

Defence date

2002-12-20

Department

  • Department of Women's and Children's Health

Publisher/Institution

Karolinska Institutet

Publication year

2002

Thesis type

  • Doctoral thesis

ISBN-10

91-7349-410-0

Number of supporting papers

6

Language

  • eng

Original publication date

2002-11-29

Author name in thesis

Nilsson, Ola

Original department name

Department of Women's and Children's Health

Place of publication

Stockholm

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