scholarly journals Insulin-Like Growth Factor-Independent Effects of Growth Hormone on Growth Plate Chondrogenesis and Longitudinal Bone Growth

Endocrinology ◽  
2015 ◽  
Vol 156 (7) ◽  
pp. 2541-2551 ◽  
Author(s):  
Shufang Wu ◽  
Wei Yang ◽  
Francesco De Luca
Keyword(s):  
Mrna Expression ◽  
Growth Plate ◽  
Molecular Mechanisms ◽  
Bone Growth ◽  
Janus Kinase ◽  
Bone Morphogenetic Protein 2 ◽  
Plate Height ◽  
Systemic Injection ◽  
Longitudinal Bone Growth ◽  
Growth Promoting

GH stimulates growth plate chondrogenesis and longitudinal bone growth directly at the growth plate. However, it is not clear yet whether these effects are entirely mediated by the local expression and action of IGF-1 and IGF-2. To determine whether GH has any IGF-independent growth-promoting effects, we generated TamCartIgf1rflox/flox mice. The systemic injection of tamoxifen in these mice postnatally resulted in the excision of the IGF-1 receptor (Igf1r) gene exclusively in the growth plate. TamCartIgf1rflox/flox tamoxifen-treated mice [knockout (KO) mice] and their Igf1rflox/flox control littermates (C mice) were injected for 4 weeks with GH. At the end of the 4-week period, the tibial growth and growth plate height of GH-treated KO mice were greater than those of untreated C or untreated KO mice. The systemic injection of GH increased the phosphorylation of Janus kinase 2 and signal transducer and activator of transcription 5B in the tibial growth plate of the C and KO mice. In addition, GH increased the mRNA expression of bone morphogenetic protein-2 and the mRNA expression and protein phosphorylation of nuclear factor-κB p65 in both C and KO mice. In cultured chondrocytes transfected with Igf1r small interfering RNA, the addition of GH in the culture medium significantly induced thymidine incorporation and collagen X mRNA expression. In conclusion, our findings demonstrate that GH can promote growth plate chondrogenesis and longitudinal bone growth directly at the growth plate, even when the local effects of IGF-1 and IGF-2 are prevented. Further studies are warranted to elucidate the intracellular molecular mechanisms mediating the IGF-independent, growth-promoting GH effects.

scholarly journals A Mixture of Humulus japonicus Increases Longitudinal Bone Growth Rate in Sprague Dawley Rats

Nutrients ◽  
2020 ◽  
Vol 12 (9) ◽  
pp. 2625
Author(s):  
Ok-Kyung Kim ◽  
Jeong moon Yun ◽  
Minhee Lee ◽  
Soo-Jeung Park ◽  
Dakyung Kim ◽  
...  
Keyword(s):  
Growth Plate ◽  
Bone Growth ◽  
Tail Length ◽  
Janus Kinase ◽  
Sprague Dawley ◽  
Plate Height ◽  
Longitudinal Bone Growth ◽  
Sd Rats ◽  
Humulus Japonicus ◽  
Igfbp 3

The aim of this study was to investigate the effects of administration of a mixture of Humulus japonicus (MH) on longitudinal bone growth in normal Sprague Dawley (SD) rats. We measured the femur and tibia length, growth plate area, proliferation of chondrocytes, and expression of insulin-like growth factor-1 (IGF-I) and IGF binding protein-3 (IGFBP-3), and Janus kinase 2 (JAK2)/signal transducer and activator of transcription 5 (STAT5) phosphorylation after dietary administration of MH in SD rats for four weeks. The nose–tail length gain and length of femur and tibia increased significantly in the group that received MH for a period of four weeks. We performed H&E staining and Bromodeoxyuridine/5-Bromo-2′-Deoxyuridine (BrdU) staining to examine the effect of dietary administration of MH on the growth plate and the proliferation of chondrocytes and found that MH stimulated the proliferation of chondrocytes and contributed to increased growth plate height during the process of longitudinal bone growth. In addition, serum levels of IGF-1 and IGFBP-3 and expression of IGF-1 and IGFBP-3 mRNAs in the liver and bone were increased, and phosphorylation of JAK2/STAT5 in the liver was increased in the MH groups. Based on these results, we suggest that the effect of MH on longitudinal bone growth is mediated by increased JAK2/STAT5-induced IGF-1 production.

scholarly journals CXXC5 mediates growth plate senescence and is a target for enhancement of longitudinal bone growth

2019 ◽  
Vol 2 (2) ◽  
pp. e201800254 ◽  
Author(s):  
Sehee Choi ◽  
Hyun-Yi Kim ◽  
Pu-Hyeon Cha ◽  
Seol Hwa Seo ◽  
Chulho Lee ◽  
...  
Keyword(s):  
Growth Plate ◽  
Molecular Mechanisms ◽  
Bone Growth ◽  
Negative Regulator ◽  
Screening Assay ◽  
Longitudinal Bone Growth ◽  
Delayed Senescence ◽  
Before And After ◽  
Delayed Growth

Longitudinal bone growth ceases with growth plate senescence during puberty. However, the molecular mechanisms of this phenomenon are largely unexplored. Here, we examined Wnt-responsive genes before and after growth plate senescence and found that CXXC finger protein 5 (CXXC5), a negative regulator of the Wnt/β-catenin pathway, was gradually elevated with reduction of Wnt/β-catenin signaling during senescent changes of rodent growth plate. Cxxc5−/− mice demonstrated delayed growth plate senescence and tibial elongation. As CXXC5 functions by interacting with dishevelled (DVL), we sought to identify small molecules capable of disrupting this interaction. In vitro screening assay monitoring CXXC5–DVL interaction revealed that several indirubin analogs were effective antagonists of this interaction. A functionally improved indirubin derivative, KY19382, elongated tibial length through delayed senescence and further activation of the growth plate in adolescent mice. Collectively, our findings reveal an important role for CXXC5 as a suppressor of longitudinal bone growth involving growth plate 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.

Peptides from Euphausia superba Promote Longitudinal Bone Growth by Accelerating Growth Plate Chondrocyte Proliferation and Hypertrophy

2020 ◽  
Vol 21 ◽  
Author(s):  
Yufeng Dai ◽  
Zhuo Li ◽  
Meng Fu ◽  
Yanqi Li ◽  
Changhu Xue ◽  
...  
Keyword(s):  
Short Stature ◽  
Growth Plate ◽  
Bone Growth ◽  
Euphausia Superba ◽  
Nutritional Intervention ◽  
Bone Morphogenetic Protein 2 ◽  
Mice Model ◽  
Serum Growth Hormone ◽  
Longitudinal Bone Growth ◽  
Related Transcription Factor

Background: With the improvements in living standards, height is getting more attention. Malnutrition is one of the main causes of children's short stature, therefore nutritional intervention in adolescence is the key to prevent short stature. The peptides from Antarctic krill (AKPs), the ideal protein model, act in bone formation and anti-osteoporosis. However, the studies on promoting longitudinal bone growth by AKPs have not been reported. Methods: Three-week-old male ICR mice, to construct the adolescent mice model, randomly divided into three groups: normal group, casein group (casein, 300 mg/kgꞏBW), and AKPs group (AKPs, 300 mg/kgꞏBW). After 21 days of drugs administration, the effects of AKPs on serum biochemical indexes and femur histomorphology of mice, and the mechanism of AKPs promoting longitudinal bone growth was discussed. Results: AKPs significantly increased the longitudinal bone growth and improved bone strength. In addition, AKPs remarkably promoted proliferation and hypertrophy of chondrocytes in the growth plate. The further mechanism revealed that AKPs increased serum growth hormone (GH) and insulin-like growth factors-1(IGF-1) contents, which activated the downstream GH/IGF-1 axis signaling pathways. Moreover, AKPs induced the secretion and expression of bone morphogenetic protein 2 (BMP-2) and triggered the activation of BMP2-dependent Smads signaling. AKPs also activated Wnt/βcatenin signaling, and synergistically activated the expression of runt-related transcription factor 2 (Runx 2) and osterix (OSX). Conclusion: AKPs promoted longitudinal bone growth by activating GH/IGF-1 axis, BMP-2/Smads and Wnt/β-catenin pathways, suggesting AKPs to be a potential nutrient fortifier for longitudinal bone growth.

scholarly journals Indirubin-3′-oxime stimulates chondrocyte maturation and longitudinal bone growth via activation of the Wnt/β-catenin pathway

2019 ◽  
Vol 51 (9) ◽  
pp. 1-10
Author(s):  
Sehee Choi ◽  
Pu-Hyeon Cha ◽  
Hyun-Yi Kim ◽  
Kang-Yell Choi
Keyword(s):  
Growth Plate ◽  
Bone Growth ◽  
Ex Vivo ◽  
Hormone Treatment ◽  
Current Approach ◽  
Plate Height ◽  
Growth Plate Chondrocytes ◽  
Longitudinal Bone Growth ◽  
Chondrocyte Maturation

Abstract Researchers have shown increased interest in determining what stimulates height. Currently, many children undergo precocious puberty, resulting in short stature due to premature closure of the growth plate. However, the current approach for height enhancement is limited to growth hormone treatment, which often results in side effects and clinical failure and is costly. Although recent studies have indicated the importance of paracrine signals in the growth plate for longitudinal bone growth, height-stimulating agents targeting the signaling pathways involved in growth plate maturation remain unavailable in the clinic. The Wnt/β-catenin pathway plays a major role in the maturation of growth plate chondrocytes. In this study, by using an ex vivo tibial culture system, we identified indirubin-3′-oxime (I3O) as a compound capable of enhancing longitudinal bone growth. I3O promoted chondrocyte proliferation and differentiation via activation of the Wnt/β-catenin pathway in vitro. Intraperitoneal injection of I3O in adolescent mice increased growth plate height along with incremental chondrocyte maturation. I3O promoted tibial growth without significant adverse effects on bone thickness and articular cartilage. Therefore, I3O could be a potential therapeutic agent for increasing height in children with growth retardation.

Fluoride Inhibits Longitudinal Bone Growth by Acting Directly at the Growth Plate in Cultured Neonatal Rat Metatarsal Bones

2019 ◽  
Vol 197 (2) ◽  
pp. 522-532 ◽  
Author(s):  
Rui Ma ◽  
Shuang Liu ◽  
Tingting Qiao ◽  
Demin Li ◽  
Ruixue Zhang ◽  
...  
Keyword(s):  
Growth Plate ◽  
Bone Growth ◽  
Neonatal Rat ◽  
Longitudinal Bone Growth ◽  
Metatarsal Bones

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.

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