Normal Bone Growth Requires Optimal Estrogen Levels: Negative Effects of Both High and Low Dose Estrogen on the Number of Growth Plate Chondrocytes

Abstract

Endochondral bone formation at epiphyseal growth plate consists of the synchronized processes of chondrogenesis and cartilage ossifi cation. Estrogen, the major female sex hormone, plays an important role in this process, particularly during the pubertal growth spurt. However, its effects on the growth plate are not completely understood. The aims of this study were to clarify the effects of estrogen on the kinetics of chondrocytes in the growth plates of 10-to 25-week-old female rabbits by studying the effects of ovariectomy or highdose administration of estrogen on the balance between cell proliferation and death. Fortyeight Japanese white rabbits were divided into three groups: sham operated, ovariectomized, or ovariectomized with subsequent weekly injection of high dose estrogen from 10 weeks. The chondrocyte kinetics was investigated by histomorphometry and immunohistochemistry, using antibodies for caspase-3, a marker of apoptosis, and for proliferating cell nuclear antigen. Both ovariectomized and estrogen-injected rabbits showed a declination of the chondrocyte number although the latter animals indicated a more dramatic effect. Estrogen-injected rabbits showed a decrease in the cell proliferating ability together with an increase in chondrocytes undergoing apoptosis while ovariectomy mainly reduced the cell proliferating ability. Given the known importance of estrogen for bone growth, one would expect that ovariectomy and high-dose administration of estrogen would have opposite effects. However, the present study indicated that both low and high concentration had a similar effect: a decrease in the chondrocyte number compared with control, suggesting that estrogen has to be maintained within a narrow range for optimal bone growth. growth plate; chondrocyte; estrogen; ovariectomy; apoptosis.Tohoku

Osteoporosis increases chondrocyte proliferation without a change in apoptosis during fracture healing in an ovariectomized rat model

“…Thus, the level of estrogen may have had an influence on chondrocyte proliferation and differentiation. As reported by previous studies (12)(13)(14), ovariectomy significantly stimulates chondrocyte proliferation and matrix synthesis in the growth plate cartilage, probably through IGF-I (13). This may be one of the reasons contributing to chondrocyte proliferation and inhibition of the removal of hypertrophic chondrocytes.…”

The Effect of Estradiol on the Growth Plate Chondrocytes of Limb and Spine from Postnatal Mice in vitro: The Role of Estrogen-Receptor and Estradiol Concentration

“…The different levels of estrogen we selected based on the previous research 15, 32, 33. Physiologic concentrations of estrogen without serum appeared to have no effect on chondrocyte proliferation, or viability.…”

Growth-Attenuation Therapy: Principles for Practice

“…Low concentrations of estrogen enhance chondrocyte growth, whereas high concentrations inhibit cartilage cell division and promote maturation and senescence of chondrocytes. 4 The central role for estrogen (as opposed to androgens) in the growth-plate-maturation process was illustrated by case reports of male subjects in their mid-20s with either decreased estrogen synthesis (aromatase deficiency) 5 or action (ER defect) 6 who were experiencing prolonged linear growth and marked delays in skeletal maturation.…”