scholarly journals Proepithelin Stimulates Growth Plate Chondrogenesis via Nuclear Factor-κB-p65-dependent Mechanisms

2011 ◽  
Vol 286 (27) ◽  
pp. 24057-24067 ◽  
Author(s):  
Shufang Wu ◽  
Weijin Zang ◽  
Xu Li ◽  
Hongzhi Sun
Keyword(s):  
Cell Proliferation ◽  
Growth Plate ◽  
Bone Growth ◽  
Nuclear Translocation ◽  
Nuclear Factor Κb ◽  
Pyrrolidine Dithiocarbamate ◽  
Growth Plate Chondrocytes ◽  
Cell Proliferation And Differentiation ◽  
Rat Growth ◽  
And Function

Proepithelin, a previously unrecognized growth factor in cartilage, has recently emerged as an important regulator for cartilage formation and function. In the present study, we provide several lines of evidences in proepithelin-mediated induction of cell proliferation, differentiation, and apoptosis in the metatarsal growth plate. Proepithelin-mediated stimulation of metatarsal growth and growth plate chondrogenesis was neutralized by pyrrolidine dithiocarbamate, a known NF-κB inhibitor. In rat growth plate chondrocytes, proepithelin induced NF-κB-p65 nuclear translocation, and nuclear NF-κB-p65 initiated its target gene cyclin D1 to regulate chondrocyte functions. The inhibition of NF-κB-p65 expression and activity (by p65 short interfering RNA (siRNA) and pyrrolidine dithiocarbamate, respectively) in chondrocytes reversed the proepithelin-mediated induction of cell proliferation and differentiation and the proepithelin-mediated prevention of cell apoptosis. Moreover, the inhibition of the phosphatidylinositol 3-kinase and Akt abolished the effects of proepithelin on NF-κB activation. Finally, using siRNA and antisense strategies, we demonstrated that endogenously produced proepithelin by chondrocytes is important for chondrocyte growth in serum-deprived conditions. These results support the hypothesis that the induction of NF-κB activity of in growth plate chondrocytes is critical in proepithelin-mediated growth plate chondrogenesis and longitudinal bone growth.

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 Defined Carboxy-Terminal Fragments of Insulin-Like Growth Factor (IGF) Binding Protein-2 Exert Similar Mitogenic Activity on Cultured Rat Growth Plate Chondrocytes as IGF-I

Endocrinology ◽  
2008 ◽  
Vol 149 (10) ◽  
pp. 4901-4911 ◽  
Author(s):  
Daniela Kiepe ◽  
Anke Van Der Pas ◽  
Sonia Ciarmatori ◽  
Ludger Ständker ◽  
Burkhardt Schütt ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Biological Activity ◽  
Growth Plate ◽  
Longitudinal Growth ◽  
Growth Plate Chondrocytes ◽  
Igf I ◽  
Rat Growth ◽  
Igf Binding ◽  
Carboxy Terminal ◽  
Igf Binding Protein

The IGF/IGF binding protein (IGFBP) system is an important component in the hormonal regulation of longitudinal growth. Evidence from in vitro studies indicates that IGFBPs may have IGF-independent effects. We analyzed the biological activity of intact IGFBP-2 and defined carboxy-terminal IGFBP-2 fragments isolated from human hemofiltrate in two cell culture systems of the growth plate: rat growth plate chondrocytes in primary culture and the mesenchymal chondrogenic cell line RCJ3.1C5.18. The IGFBP-2 fragments IGFBP-2167–279, IGFBP-2167–289, and IGFBP-2104–289 exerted a strong (2- to 3-fold) mitogenic effect on growth plate chondrocytes, which was comparable with IGF-I in equimolar concentrations (7.8 nm) but was not mediated through the type 1 IGF receptor. In a dose-response experiment, the most effective concentration of IGFBP-2104–289 for the stimulation of cell proliferation was 10 nm. This biological activity of IGFBP-2 fragments was associated with cell membrane binding, demonstrated by Western blot analysis of fractionated cell lysates and immunohistochemistry. Whereas intact IGFBP-2 did not modulate chondrocyte proliferation, partially reduced (by dithiothreitol) full-length IGFBP-2 stimulated cell proliferation to a comparable extent (3.4-fold) as carboxy-terminal IGFBP-2 fragments. The mitogenic activity of these IGFBP-2 fragments and of partially reduced full-length IGFBP-2 was mediated through the use of the MAPK/ERK 1/2. These data imply a novel role of naturally occurring IGFBP-2 fragments for the endocrine and paracrine/autocrine regulation of longitudinal growth.

scholarly journals Temporal Analysis of Rat Growth Plates: Cessation of Growth with Age Despite Presence of a Physis

2003 ◽  
Vol 51 (3) ◽  
pp. 373-383 ◽  
Author(s):  
Helmtrud I. Roach ◽  
Gautam Mehta ◽  
Richard O.C. Oreffo ◽  
Nicholas M.P. Clarke ◽  
Cyrus Cooper
Keyword(s):  
Bone Formation ◽  
Growth Plate ◽  
Bone Growth ◽  
Temporal Analysis ◽  
Aged Rats ◽  
Growth Plate Chondrocytes ◽  
Growth Plates ◽  
Rat Growth ◽  
Old Rats ◽  
Plate Morphology

Despite the continued presence of growth plates in aged rats, longitudinal growth no longer occurs. The aims of this study were to understand the reasons for the cessation of growth. We studied the growth plates of femurs and tibiae in Wistar rats aged 62–80 weeks and compared these with the corresponding growth plates from rats aged 2–16 weeks. During skeletal growth, the heights of the plates, especially that of the hypertrophic zone, reflected the rate of bone growth. During the period of decelerating growth, it was the loss of large hydrated chondrocytes that contributed most to the overall decrease in the heights of the growth plates. In the old rats we identified four categories of growth plate morphology that were not present in the growth plates of younger rats: (a) formation of a bone band parallel to the metaphyseal edge of the growth plate, which effectively sealed that edge; (b) extensive areas of acellularity, which were resistant to resorption and/or remodeling; (c) extensive remodeling and bone formation within cellular regions of the growth plate; and (d) direct bone formation by former growth plate chondrocytes. These processes, together with a loss of synchrony across the plate, would prevent further longitudinal expansion of the growth plate despite continued sporadic proliferation of chondrocytes.

scholarly journals Palmitic Acid Induces Production of Proinflammatory Cytokines Interleukin-6, Interleukin-1β, and Tumor Necrosis Factor-αvia a NF-κB-Dependent Mechanism in HaCaT Keratinocytes

2013 ◽  
Vol 2013 ◽  
pp. 1-11 ◽  
Author(s):  
Bing-rong Zhou ◽  
Jia-an Zhang ◽  
Qian Zhang ◽  
Felicia Permatasari ◽  
Yang Xu ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Tumor Necrosis Factor ◽  
Palmitic Acid ◽  
Interleukin 6 ◽  
Tumor Necrosis ◽  
Nuclear Translocation ◽  
Pyrrolidine Dithiocarbamate ◽  
Hacat Keratinocytes ◽  
Stat3 Phosphorylation ◽  
Necrosis Factor

To investigate whether palmitic acid can be responsible for the induction of inflammatory processes, HaCaT keratinocytes were treated with palmitic acid at pathophysiologically relevant concentrations. Secretion levels of interleukin-6 (IL-6), tumor necrosis factor-α(TNF-α), interleukin-1β(IL-1β), NF-κB nuclear translocation, NF-κB activation, Stat3 phosphorylation, and peroxisome proliferator-activated receptor alpha (PPARα) mRNA and protein levels, as well as the cell proliferation ability were measured at the end of the treatment and after 24 hours of recovery. Pyrrolidine dithiocarbamate (PDTC, a selective chemical inhibitor of NF-κB) and goat anti-human IL-6 polyclonal neutralizing antibody were used to inhibit NF-κB activation and IL-6 production, respectively. Our results showed that palmitic acid induced an upregulation of IL-6, TNF-α, IL-1βsecretions, accompanied by NF-κB nuclear translocation and activation. Moreover, the effect of palmitic acid was accompanied by PPARαactivation and Stat3 phosphorylation. Palmitic acid-induced IL-6, TNF-α, IL-1βproductions were attenuated by NF-κB inhibitor PDTC. Palmitic acid was administered in amounts able to elicit significant hyperproliferation and can be attenuated by IL-6 blockage. These data demonstrate for the first time that palmitic acid can stimulate IL-6, TNF-α, IL-1βproductions in HaCaT keratinocytes and cell proliferation, thereby potentially contributing to acne inflammation and pilosebaceous duct hyperkeratinization.

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.

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

Endocrinology ◽  
2008 ◽  
Vol 149 (4) ◽  
pp. 1820-1828 ◽  
Author(s):  
Rose Marino ◽  
Anita Hegde ◽  
Kevin M. Barnes ◽  
Lenneke Schrier ◽  
Joyce A. Emons ◽  
...  
Keyword(s):  
Growth Rate ◽  
Growth Inhibition ◽  
Growth Plate ◽  
Bone Growth ◽  
Structural Characteristics ◽  
Linear Growth Rate ◽  
Growth Plate Chondrocytes ◽  
Growth Plates ◽  
Catch Up ◽  
Growth Inhibiting

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.

scholarly journals Valproic Acid Impacts the Growth of Growth Plate Chondrocytes

2020 ◽  
Vol 17 (10) ◽  
pp. 3675
Author(s):  
Hueng-Chuen Fan ◽  
Shih-Yu Wang ◽  
Yi-Jen Peng ◽  
Herng-Sheng Lee
Keyword(s):  
Valproic Acid ◽  
Short Stature ◽  
Growth Plate ◽  
Caspase 3 ◽  
Skeletal Growth ◽  
Growth Plate Chondrocytes ◽  
Protein Levels ◽  
Rat Growth ◽  
Cox 2 ◽  
Bone Abnormalities

A range of bone abnormalities including short stature have been reported to be associated with the use of antiepileptic drugs (AEDs) in children. Exactly how AEDs impact skeletal growth, however, is not clear. In the present study, rat growth plate chondrocytes were cultured to study the effects of AEDs, including valproic acid (VPA), oxcarbazepine (OXA), levetiracetam (LEV), lamotrigine (LTG), and topiramate (TPM) on the skeletal growth. VPA markedly reduced the number of chondrocytes by apoptosiswhile other AEDs had no effect. The apoptosis associated noncleaved and cleaved caspase 3, and caspases were increased by exposure to VPA, which up-regulated cyclooxygenase 2 (COX-2) mRNA and protein levels likely through histone acetylation. The COX-2 inhibitor NS-398 attenuated the effects of VPA up-regulating COX-2 expression and decreased VPA-induced caspase 3 expression. The use of VPA in children should be closely monitored or replaced, where appropriate, by AEDs which do not apparently affect the growth plate chondrocytes.

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