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

Wu, Shufang; Flint, Janna K.; Rezvani, Geoffrey; Luca, Francesco De

doi:10.1074/jbc.m702991200

Cited by 54 publications

(54 citation statements)

References 35 publications

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“…We have previously demonstrated that BMP-2 stimulates longitudinal bone growth and growth plate chondrogenesis (43), and BMP-2 expression and activity in growth plate chondrocyte function are regulated by NF-B p65 (7). In this study, we show that the NF-B p65 activation by GH also induces BMP-2 expression, which suggests that GH may promote growth plate chondrocyte function by activating both IGF-1 and BMP-2 activity.…”

Section: Discussionsupporting

confidence: 56%

“…We have previously shown that NF-B p65 is expressed in the murine growth plate, and it facilitates growth plate chondrogenesis (7). In addition, we have demonstrated that skin fibroblasts isolated from a child harboring a heterozygous mutation of IB␣ (responsible for impaired NF-B p65 activity) exhibited an absent proliferative response to GH in vitro (11).…”

Section: Discussionmentioning

confidence: 76%

“…We have recently demonstrated that NF-B p65 is expressed in the murine growth plate, and it facilitates longitudinal bone growth and growth plate chondrogenesis in part by inducing bone morphogenetic protein-2 (BMP-2) expression (7). In addition, we have also shown that NF-B p65 mediates the growth-promoting effects of insulin-like growth factor-1 (IGF-1) on chondrogenesis and longitudinal bone growth (8).…”

mentioning

confidence: 99%

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Nuclear Factor-κB (NF-κB) p65 Interacts with Stat5b in Growth Plate Chondrocytes and Mediates the Effects of Growth Hormone on Chondrogenesis and on the Expression of Insulin-like Growth Factor-1 and Bone Morphogenetic Protein-2

Morrison

Sun

et al. 2011

Journal of Biological Chemistry

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Growth hormone (GH) stimulates growth plate chondrogenesis and longitudinal bone growth with its stimulatory effects primarily mediated by insulin-like growth factor-1 (IGF-1) both systemically and locally in the growth plate. It has been shown that the transcription factor Stat5b mediates the GH promoting effect on IGF-1 expression and on chondrogenesis, yet it is not known whether other signaling molecules are activated by GH in growth plate chondrocytes. We have previously demonstrated that nuclear factor-B p65 is a transcription factor expressed in growth plate chondrocytes where it facilitates chondrogenesis. We have also shown that fibroblasts isolated from a patient with growth failure and a heterozygous mutation of inhibitor-B␣ (IB; component of the nuclear factor-B (NF-B) signaling pathway) exhibit GH insensitivity. In this study, we cultured rat metatarsal bones in the presence of GH and/or pyrrolidine dithiocarbamate (PDTC), a known NF-B inhibitor. The GHmediated stimulation of metatarsal longitudinal growth and growth plate chondrogenesis was neutralized by PDTC. In cultured chondrocytes isolated from rat metatarsal growth plates, GH induced NF-B-DNA binding and chondrocyte proliferation and differentiation and prevented chondrocyte apoptosis. The inhibition of NF-B p65 expression and activity (by NF-B p65 siRNA and PDTC, respectively) in chondrocytes reversed the GH-mediated effects on chondrocyte proliferation, differentiation, and apoptosis. Lastly, the inhibition of Stat5b expression in chondrocytes prevented the GH promoting effects on NF-B-DNA binding, whereas the inhibition of NF-B p65 expression or activity prevented the GH-dependent activation of IGF-1 and bone morphogenetic protein-2 expression.

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Section: Discussionsupporting

confidence: 56%

Section: Discussionmentioning

confidence: 76%

mentioning

confidence: 99%

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Nuclear Factor-κB (NF-κB) p65 Interacts with Stat5b in Growth Plate Chondrocytes and Mediates the Effects of Growth Hormone on Chondrogenesis and on the Expression of Insulin-like Growth Factor-1 and Bone Morphogenetic Protein-2

Morrison

Sun

et al. 2011

Journal of Biological Chemistry

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“…In addition, we interestingly observed that functionally intact IKK␤ and NEMO are required for viability maintenance in multiple (16,17,28,43). While these previous studies did not address molecular mechanisms responsible for constitutive IKK and/or NF-B activation in chondrocytes, our current study may provide a molecular explanation as to how a nuclear factor such as Nkx3.2 can enable steady-state IKK activation leading to constitutive NF-B activation, which can be associated with cell viability maintenance in chondrocytes (28,43). The results shown in this work may enhance our mechanistic understanding as to how the NF-B pathway functions during bone development.…”

Section: Discussionmentioning

confidence: 96%

Exogenous Signal-Independent Nuclear IκB Kinase Activation Triggered by Nkx3.2 Enables Constitutive Nuclear Degradation of IκB-α in Chondrocytes

Yong

Choi

et al. 2011

Molecular and Cellular Biology

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NF-B is a multifunctional transcription factor involved in diverse biological processes. It has been well documented that NF-B can be activated in response to various stimuli. While signal-inducible NF-B activation mechanisms have been extensively characterized, exogenous signal-independent intrinsic NF-B activation processes remain poorly understood. Here we show that I B kinase ␤ (IKK␤) can be intrinsically activated in the nucleus by a homeobox protein termed Nkx3.2 in the absence of exogenous IKK-activating signals. We found that ubiquitin chain-dependent, but persistent, interactions between Nkx3.2 and NEMO (also known as IKK␥) can give rise to constitutive IKK␤ activation in the nucleus. Once the Nkx3.2-NEMO-IKK␤ complex is formed in the nucleus, IKK␤-induced Nkx3.2 phosphorylation at Ser148 and Ser168 allows ␤TrCP to be engaged to cause I B-␣ ubiquitination independent of I B-␣ phosphorylation at Ser32 and Ser36. Taken together, our results provide a novel molecular explanation as to how an intracellular factor such as Nkx3.2 can accomplish persistent nuclear IKK activation to enable intrinsic and constitutive degradation of I B in the nucleus in the absence of exogenous NF-B-activating signals, which, in turn, plays a role in chondrocyte viability maintenance.NF-B regulates expression of a variety of genes associated with immune responses, proliferation, differentiation, and apoptosis (21, 23, 39). Numerous studies have described in detail the molecular mechanisms of signal-dependent NF-B activation. In particular, it is well established that diverse NF-B-activating signals trigger I B kinase ␤ (IKK␤) activation in the cytoplasm to permit signal-dependent I B-␣ phosphorylation, which, in turn, causes its ubiquitination and proteasomal degradation, leading to 11,13,18,21,23,39). While these extensive studies pertain to the signal-inducible NF-B activation process, exogenous signal-independent intrinsic NF-B activation mechanisms are largely unknown.Nkx3.2 (also termed Bapx1) is initially expressed in chondrocyte precursor cells during development, and later, its expression is maintained in chondrocytes of various skeletal elements (19,20,25,29,37,47). We have previously demonstrated that Nkx3.2 supports chondrocyte survival by constitutively activating p65-RelA, leaving p105 and p100 NF-B unaffected (28). However, it remains to be understood how Nkx3.2, a nuclear homeobox protein, can indeed trigger constitutive I B degradation and give rise to intrinsic NF-B activation in chondrocytes in the absence of exogenous NF-Bactivating signals.It has been suggested that polyubiquitin chains play a role in creating multiprotein complexes in signal-inducible NF-B activation pathways (4,9,27,34,35,41,48). For instance, the ability of NEMO (also known as IKK␥) to recognize and interact with polyubiquitin chains has been shown to be critical for NEMO to establish functionally active IKK complexes in the cytoplasm in response to NF-B-activating signals (4,9,34,41,48). While these findings pertain to signal-inducible ev...

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“…However, BMP2 also drives terminal differentiation, supporting the expression of collagen X. NF-κB mediates the regulation of growth plate chondrogenesis by IGF-1, which stimulates longitudinal bone growth by inducing chondrocyte proliferation and maturation and inhibiting apoptosis. The IGF-1 receptor is a receptor tyrosine kinase that activates an array of intracellular signaling pathways, and recent studies have shown that the major effects of IGF-1 on the growth plate appear to be mediated by p65 [54,55]. Chemical inhibition of NF-κB blocks the stimulatory effects of IGF-1 on chondrocyte proliferation and hypertrophy in rat metatarsal explant cultures and its inhibitory effect on apoptosis in cultured chondrocytes.…”

Section: Nf-κb In Chondrocytesmentioning

confidence: 99%

Role of NF-κB in the skeleton

2010

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Since the discovery that deletion of the NF-κB subunits p50 and p52 causes osteopetrosis in mice, there has been considerable interest in the role of NF-κB signaling in bone. NF-κB controls the differentiation or activity of the major skeletal cell types -osteoclasts, osteoblasts, osteocytes and chondrocytes. However, with five NF-κB subunits and two distinct activation pathways, not all NF-κB signals lead to the same physiologic responses. In this review, we will describe the roles of various NF-κB proteins in basal bone homeostasis and disease states, and explore how NF-κB inhibition might be utilized therapeutically.

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

Cited by 54 publications

References 35 publications

Nuclear Factor-κB (NF-κB) p65 Interacts with Stat5b in Growth Plate Chondrocytes and Mediates the Effects of Growth Hormone on Chondrogenesis and on the Expression of Insulin-like Growth Factor-1 and Bone Morphogenetic Protein-2

Nuclear Factor-κB (NF-κB) p65 Interacts with Stat5b in Growth Plate Chondrocytes and Mediates the Effects of Growth Hormone on Chondrogenesis and on the Expression of Insulin-like Growth Factor-1 and Bone Morphogenetic Protein-2

Exogenous Signal-Independent Nuclear IκB Kinase Activation Triggered by Nkx3.2 Enables Constitutive Nuclear Degradation of IκB-α in Chondrocytes

Role of NF-κB in the skeleton

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