scholarly journals DHEA Suppresses Longitudinal Bone Growth by Acting Directly at Growth Plate through Estrogen Receptors

Endocrinology ◽  
2011 ◽  
Vol 152 (4) ◽  
pp. 1423-1433 ◽  
Author(s):  
Hongzhi Sun ◽  
Weijin Zang ◽  
Bo Zhou ◽  
Lin Xu ◽  
Shufang Wu
Keyword(s):  
Estrogen Receptor ◽  
Growth Plate ◽  
Bone Growth ◽  
Nuclear Factor Κb ◽  
Binding Activity ◽  
Skeletal Maturation ◽  
Chondrocyte Apoptosis ◽  
Chondrocyte Proliferation ◽  
Longitudinal Bone Growth ◽  
Growth Plate Chondrocyte

Abstract Dehydroepiandrosterone (DHEA) is produced by the adrenal cortex and is the most abundant steroid in humans. Although in some physiological and pathological conditions the increased secretion of DHEA and its sulfated form is associated with accelerated growth rate and skeletal maturation, it is unclear whether DHEA can affect longitudinal bone growth and skeletal maturation by acting directly at the growth plate. In our study, DHEA suppressed metatarsal growth, growth plate chondrocyte proliferation, and hypertrophy/differentiation. In addition, DHEA increased the number of apoptotic chondrocytes in the growth plate. In cultured chondrocytes, DHEA reduced chondrocyte proliferation and induced apoptosis. The DHEA-induced inhibition of metatarsal growth and growth plate chondrocyte proliferation and hypertrophy/differentiation was nullified by culturing metatarsals with DHEA in the presence of ICI 182,780, an inhibitor of estrogen receptor, but not in the presence of Casodex, an inhibitor of androgen receptor. Lastly, nuclear factor-κB DNA binding activity was inhibited by the addition of DHEA in the medium of cultured chondrocyte. Our findings indicate that DHEA suppressed bone growth by acting directly at growth plate through estrogen receptor. Such growth inhibition is mediated by decreased chondrocyte proliferation and hypertrophy/differentiation and by increased chondrocyte apoptosis.

scholarly journals Nuclear Factor-κB p65 Facilitates Longitudinal Bone Growth by Inducing Growth Plate Chondrocyte Proliferation and Differentiation and by Preventing Apoptosis

2007 ◽  
Vol 282 (46) ◽  
pp. 33698-33706 ◽  
Author(s):  
Shufang Wu ◽  
Janna K. Flint ◽  
Geoffrey Rezvani ◽  
Francesco De Luca
Keyword(s):  
Growth Plate ◽  
Bone Growth ◽  
Chondrocyte Apoptosis ◽  
Pyrrolidine Dithiocarbamate ◽  
Growth Plate Chondrocytes ◽  
Chondrocyte Proliferation ◽  
Longitudinal Bone Growth ◽  
Metatarsal Bones ◽  
Proliferation And Differentiation ◽  
Cultured Chondrocytes

NF-κB is a group of transcription factors involved in cell proliferation, differentiation, and apoptosis. Mice deficient in the NF-κB subunits p50 and p52 have retarded growth, suggesting that NF-κB is involved in bone growth. Yet, it is not clear whether the reduced bone growth of these mice depends on the lack of NF-κB activity in growth plate chondrocytes. Using cultured rat metatarsal bones and isolated growth plate chondrocytes, we studied the effects of two NF-κB inhibitors (pyrrolidine dithiocarbamate (PDTC) or BAY11-7082 (BAY)), p65 short interference RNA (siRNA), and of the overexpression of p65 on chondrocyte proliferation, differentiation, and apoptosis. To further define the underlying mechanisms, we studied the functional interaction between NF-κB p65 and BMP-2 in chondrocytes. PDTC and BAY suppressed metatarsal linear growth. Such growth inhibition resulted from decreased chondrocyte proliferation and differentiation and from increased chondrocyte apoptosis. In cultured chondrocytes, the inhibition of NF-κB p65 activation (by PDTC and BAY) and expression (by p65 siRNA) led to the same findings observed in cultured metatarsal bones. In contrast, overexpression of p65 in cultured chondrocytes induced chondrocyte proliferation and differentiation and prevented apoptosis. Although PDTC, BAY, and p65 siRNA reduced the expression of BMP-2 in cultured growth plate chondrocytes, the overexpression of p65 increased it. The addition of Noggin, a BMP-2 antagonist, neutralized the stimulatory effects of p65 on chondrocyte proliferation and differentiation, as well as its anti-apoptotic effect. In conclusion, our findings indicate that NF-κB p65 expressed in growth plate chondrocytes facilitates growth plate chondrogenesis and longitudinal bone growth by inducing BMP-2 expression and activity.

scholarly journals The role of estrogen receptor-α and its activation function-1 for growth plate closure in female mice

2012 ◽  
Vol 302 (11) ◽  
pp. E1381-E1389 ◽  
Author(s):  
A. E. Börjesson ◽  
S. H. Windahl ◽  
E. Karimian ◽  
E. E. Eriksson ◽  
M. K. Lagerquist ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Growth Plate ◽  
Bone Growth ◽  
High Dose ◽  
Plate Height ◽  
Chondrocyte Proliferation ◽  
Growth Plates ◽  
Longitudinal Bone Growth ◽  
Female Mice

High estradiol levels in late puberty induce growth plate closure and thereby cessation of growth in humans. In mice, the growth plates do not fuse after sexual maturation, but old mice display reduced longitudinal bone growth and high-dose estradiol treatment induces growth plate closure. Estrogen receptor (ER)-α stimulates gene transcription via two activation functions (AFs), AF-1 and AF-2. To evaluate the role of ERα and its AF-1 for age-dependent reduction in longitudinal bone growth and growth plate closure, female mice with inactivation of ERα (ERα−/−) or ERαAF-1 (ERαAF-10) were evaluated. Old (16- to 19-mo-old) female ERα−/− mice showed continued substantial longitudinal bone growth, resulting in longer bones (tibia: +8.3%, P < 0.01) associated with increased growth plate height (+18%, P < 0.05) compared with wild-type (WT) mice. In contrast, the longitudinal bone growth ceased in old ERαAF-10 mice (tibia: −4.9%, P < 0.01). Importantly, the proximal tibial growth plates were closed in all old ERαAF-10 mice while they were open in all WT mice. Growth plate closure was associated with a significantly altered balance between chondrocyte proliferation and apoptosis in the growth plate. In conclusion, old female ERα−/− mice display a prolonged and enhanced longitudinal bone growth associated with increased growth plate height, resembling the growth phenotype of patients with inactivating mutations in ERα or aromatase. In contrast, ERαAF-1 deletion results in a hyperactive ERα, altering the chondrocyte proliferation/apoptosis balance, leading to growth plate closure. This suggests that growth plate closure is induced by functions of ERα that do not require AF-1 and that ERαAF-1 opposes growth plate closure.

scholarly journals Evidence supporting dual, IGF-I-independent and IGF-I-dependent, roles for GH in promoting longitudinal bone growth

2004 ◽  
Vol 180 (2) ◽  
pp. 247-255 ◽  
Author(s):  
J Wang ◽  
J Zhou ◽  
CM Cheng ◽  
JJ Kopchick ◽  
CA Bondy
Keyword(s):  
Growth Hormone ◽  
Growth Plate ◽  
Bone Growth ◽  
Long Bone ◽  
Null Mouse ◽  
Chondrocyte Proliferation ◽  
Chondrocyte Hypertrophy ◽  
Longitudinal Bone Growth ◽  
Germinal Zone ◽  
Igf I

The possibility that growth hormone (GH) has effects on long bone growth independent of insulin-like growth factor-I (IGF-I) has long been debated. If this is true, then long bone growth should be more profoundly affected by the absence of GH (since both GH and GH-stimulated IGF-I effects are absent) than by the absence of IGF-I alone (since GH is still present and actually elevated). To test this hypothesis, we compared long bone growth in mice with targeted deletions of Igf1 vs growth hormone receptor (Ghr). Tibial linear growth rate was reduced by approximately 35% in Igf1 null mice and by about 65% in Ghr null mice between postnatal days 20 and 40, a time of peak GH effect during normal longitudinal growth. The Igf1 null mouse growth plate demonstrated significant enlargement of the germinal zone; chondrocyte proliferation and numbers were normal but chondrocyte hypertrophy was significantly reduced. In contrast, the Ghr null mouse germinal zone was hypoplastic, chondrocyte proliferation and numbers were significantly reduced, and chondrocyte hypertrophy was also reduced. We have previously demonstrated that IGF-II is highly expressed in growth plate germinal and proliferative zones, so we considered the possibility that GH-stimulated IGF-II production might promote germinal zone expansion and maintain normal proliferation in the Igf1 null mouse growth plate. Supporting this view, IGF-II mRNA was increased in the Igf1 null mouse and decreased in the Ghr null mouse growth plate.Thus, in the complete absence of IGF-I but in the presence of elevated GH in the Igf1 null mouse, reduction in chondrocyte hypertrophy appears to be the major defect in longitudinal bone growth. In the complete absence of a GH effect in the Ghr null mouse, however, both chondrocyte generation and hypertrophy are compromised, leading to a compound deficit in long bone growth. These observations support dual roles for GH in promoting longitudinal bone growth: an IGF-I-independent role in growth plate chondrocyte generation and an IGF-I-dependent role in promoting chondrocyte hypertrophy. The question of whether GH has direct effects on chondrocyte generation is still not settled, however, since it now appears that IGF-II may medicate some of these effects on the growth plate.

scholarly journals GPR30 Estrogen Receptor Expression in the Growth Plate Declines as Puberty Progresses

2007 ◽  
Vol 92 (12) ◽  
pp. 4873-4877 ◽  
Author(s):  
Andrei S. Chagin ◽  
Lars Sävendahl
Keyword(s):  
Growth Plate ◽  
Bone Growth ◽  
Receptor Expression ◽  
Skeletal Maturation ◽  
Tall Stature ◽  
Leg Length ◽  
Epiphyseal Growth Plate ◽  
Growth Plates ◽  
Longitudinal Bone Growth ◽  
Proliferative Zone

Abstract Objective: Our objective was to study whether GPR30 is expressed in the epiphyseal growth plate and its potential role as a modulator of pubertal growth. Background: Estrogens play a crucial role in the regulation of skeletal maturation and longitudinal bone growth. We have previously shown that both estrogen receptors (ERs) α and β are expressed in the human epiphyseal growth plate. Recently, a membrane-bound ER referred to as GPR30 was discovered, but the role played by this receptor in the regulation of longitudinal bone growth is not yet known. Patients/Methods: Biopsies were collected from the tibial growth plates of 14 boys and seven girls that underwent epiphyseal surgery to arrest longitudinal bone growth. The patients were in different stages of puberty and suffered from inequality in leg length or extreme tall stature. Paraffin-embedded sections of the growth plates were used to detect expression of the GPR30 protein. Results: The highest level of GPR30 expression was observed in hypertrophic chondrocytes, although cells with positive immunostaining were also detected in the resting zone. In contrast, no immunoreactivity was found in the proliferative zone. During pubertal progression there was a clear decline in the level of GPR30 expression in both boys and girls. Conclusions: The novel ER GPR30 is expressed in the human growth plate, and the level of expression declines during pubertal progression. Although a relationship between GPR30 expression and age may underlie the observed pubertal decline in the GPR30 level, our observations suggest that this receptor could be involved in the modulation of longitudinal bone growth during puberty.

The role of estrogen receptor α in growth plate cartilage for longitudinal bone growth

2010 ◽  
Vol 25 (12) ◽  
pp. 2690-2700 ◽  
Author(s):  
Anna E Börjesson ◽  
Marie K Lagerquist ◽  
Chen Liu ◽  
Ruijin Shao ◽  
Sara H Windahl ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Growth Plate ◽  
Bone Growth ◽  
Estrogen Receptor Α ◽  
Longitudinal Bone Growth ◽  
Growth Plate Cartilage

scholarly journals Estrogen receptor specificity in the regulation of the skeleton in female mice

2001 ◽  
Vol 171 (2) ◽  
pp. 229-236 ◽  
Author(s):  
MK Lindberg ◽  
SL Alatalo ◽  
JM Halleen ◽  
S Mohan ◽  
JA Gustafsson ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Alpha ◽  
Bone Growth ◽  
Fat Content ◽  
Mineral Density ◽  
Trabecular Bone Mineral Density ◽  
Longitudinal Bone Growth ◽  
Female Mice ◽  
Opposing Effects ◽  
Er Alpha

There are two known estrogen receptors, estrogen receptor-alpha (ER alpha) and estrogen receptor-beta (ER beta), which may mediate the actions of estrogen. The aim of the present study was to compare fat content, skeletal growth and adult bone metabolism in female mice lacking ER alpha (ERKO), ER beta (BERKO) or both ERs (DERKO). We demonstrate that endogenous estrogens decrease the fat content in female mice via ER alpha and not ER beta. Interestingly, the longitudinal bone growth was decreased in ERKO, increased in BERKO, but was intermediate in DERKO females, demonstrating that ER alpha and ER beta exert opposing effects in the regulation of longitudinal bone growth. The effects on longitudinal bone growth were correlated with similar effects on serum levels of IGF-I. A complex regulation of the trabecular bone mineral density (BMD), probably caused by a disturbed feedback regulation of estrogen and testosterone, was observed in female ER-inactivated mice. Nevertheless, a partial functional redundancy for ER alpha and ER beta in the maintenance of the trabecular BMD was observed in the female mice at 60 days of age. Thus, ER alpha and ER beta may have separate effects (regulation of fat), opposing effects (longitudinal bone growth) or partial redundant effects (trabecular BMD at 60 days of age), depending on which parameter is studied.

scholarly journals Long Term Cyclic Pamidronate Reduces Bone Growth by Inhibiting Osteoclast Mediated Cartilage-to-Bone Turnover in the Mouse

2008 ◽  
Vol 2 (1) ◽  
pp. 121-125 ◽  
Author(s):  
K.D Evans ◽  
L.E Sheppard ◽  
D.I Grossman ◽  
S.H Rao ◽  
R.B Martin ◽  
...  
Keyword(s):  
Bone Turnover ◽  
Growth Plate ◽  
Bone Growth ◽  
Cathepsin K ◽  
Chondrocyte Apoptosis ◽  
Cell Numbers ◽  
Hypertrophic Chondrocyte ◽  
Osteoclast Function ◽  
And Function

Bisphosphonates, used to treat diseases exhibiting increased osteoclast activity, reduce longitudinal bone growth through an as yet undefined mechanism. Pamidronate, an aminobisphosphonate, was given weekly to mice at 0, 1.25, or 2.50 mg/kg/wk beginning at 4 weeks of age. At 12 weeks of age, humeral length, growth plate area, regional chondrocyte cell numbers, chondrocyte apoptosis, TRAP stained osteoclast number, and osteoclast function assessed by cathepsin K immunohistochemistry were quantified. Humeral length was decreased in pamidronate treated mice compared to vehicle control mice, and correlated with greater growth plate areas reflecting greater proliferative and hypertrophic chondrocyte cell numbers with fewer hypertrophic cells undergoing apoptosis. Pamidronate treatment increased TRAP stained osteoclast numbers yet decreased cathepsin K indicating that pamidronate repressed osteoclast maturation and function. The data suggest that long term cyclic pamidronate treatment impairs bone growth by inhibition of osteoclast maturation thereby reducing cartilage-to-bone turnover within the growth plate.

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