IGF-1R signaling in chondrocytes modulates growth plate development by interacting with the PTHrP/Ihh pathway

Wang, Yongmei; Cheng, Zhiqiang; Elalieh, Hashem; Nakamura, Eiichiro; Nguyen, My-Linh Thi; Mackem, Susan; Clemens, Thomas L.; Bikle, Daniel D.; Chang, Wenhan

doi:10.1002/jbmr.359

Cited by 113 publications

(84 citation statements)

References 37 publications

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“…The IGF1R has been deleted using the Col2a1, and its phenotype shows growth plate defects including disorganized chondrocytes, decreased proliferation and increased apoptosis. 33 The use of a tamoxifen inducible model to delete the IGF1R in chondrocytes 1 week postnatally revealed a significant reduction in growth plate chondrocyte proliferation and differentiation. 26 Recently, IGF-1 was deleted using the Hoxb6 cre (this cre is expressed in both the hind and anterior part of the forelimb) and the phenotype revealed a critical role for IGF-1 in controlling the size of the limbs through the volume of hypertrophic chondrocytes.…”

Section: Igf-1 and Chondrocytesmentioning

confidence: 99%

IGF-1 regulation of key signaling pathways in bone

2013

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Insulin-like growth factor 1 (IGF-1) is an unique peptide that functions in an endocrine/paracrine and autocrine manner in most tissues. Although it was postulated initially that liver-derived IGF-1 was the major source of IGF-1 (that is, the somatomedin hypothesis), it is also produced in a wide variety of tissues and can function in numerous ways as both a proliferative and differentiative factor. One such tissue is bone and all cell lineages in the skeleton have been shown to not only require IGF-1 for normal development and function but also to respond to IGF-1 via the IGF-1 receptor. Ligandreceptor activation leads to several distinct downstream signaling cascades, which have significant implications for cell survival, protein synthesis and energy utilization. The novel role of IGF-1 in regulating metabolic demands of the bone remodeling unit is currently under investigation. More studies are likely to shed new light on various aspects of skeletal physiology and potentially may lead to new therapeutics.

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Section: Igf-1 and Chondrocytesmentioning

confidence: 99%

IGF-1 regulation of key signaling pathways in bone

2013

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“…We speculate that the decreased IGF1R/Akt signaling in bones of NO66-TG mice could contribute in part to the decreased mRNA expression of Runx2 and Osx, and this decrease may be then responsible for the decreased number of hypertrophic chondrocytes and Osx-expressing cells observed in these mice. In fact, the phenotype of our NO66-TG mice resembles that of cartilage-specific Igf1r knockout mice, which exhibit growth retardation with disorganized chondrocyte columns, delayed primary ossification, and decreased chondrocyte proliferation (14). We propose that the reduction of IGF1R/Akt signaling cascade in bones of NO66-TG mice contributes in part to the bone growth retardation phenotype of these mice.…”

Section: Discussionmentioning

confidence: 69%

“…7A, C; P , 0.05). These results suggested that mesenchymal overexpression of NO66 in mice may inhibit the IGF1/IGF1R/Akt signaling pathway, an important signal in the control of chondrocyte and osteoblast proliferation (14,15). Previous in vitro studies reported that NO66 has a histone demethylase activity that is specific for H3K4me3 and H3K36me3.…”

Section: Proliferation Of Skeletal Cells In No66-tg Micementioning

confidence: 81%

“…18). Expression of these factors is differentially regulated by a broad signaling network including IGF1, BMP2, and Wnt/b-catenin signaling pathways (11,(13)(14)(15). To determine changes in mRNA expression of these factors, we performed qPCR assays using total RNA from limbs of E13.5 mouse embryos.…”

Section: Proliferation Of Skeletal Cells In No66-tg Micementioning

confidence: 99%

“…In Osx-null (Osx 2/2 ) mice, expression of bone formation markers, such as type I collagen (Col1), alkaline phosphatase (Alp), bone sialoprotein (Bsp), and Osteocalcin (Oc), was inhibited, and formation of both endochondral and intramembranous bones was abolished (9). Bone formation and growth are also controlled by a broad signaling network including IGF, bone morphogenetic protein (BMP), and members of the Wnt family (11)(12)(13)(14)(15). Previous studies showed that dysregulation of these signaling molecules results in abnormal bone growth (16)(17)(18)(19).…”

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Mesenchyme‐specific overexpression of nucleolar protein 66 in mice inhibits skeletal growth and bone formation

et al. 2015

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Previous studies showed that nucleolar protein 66 (NO66), the Jumonji C-domain-containing histone demethylase for methylated histone H3K4 and H3K36 (H3K36me), negatively regulates osteoblast differentiation in vitro by inhibiting the activity of transcription factor osterix (Osx). However, whether NO66 affects mammalian skeletogenesis in vivo is not yet known. Here, we generated transgenic (TG) mice overexpressing a flag-tagged NO66 transgene driven by the Prx1 (paired related homeobox 1) promoter. We found that NO66 overexpression in Prx1-expressing mesenchymal cells inhibited skeletal growth and bone formation. The inhibitory phenotype was associated with >50% decreases in chondrocyte/osteoblast proliferation and differentiation. Moreover, we found that in bones of NO66-TG mice, expression of Igf1, Igf1 receptor (Igf1r), runt-related transcription factor 2, and Osx was significantly down-regulated (P < 0.05). Consistent with these results, we observed >50% reduction in levels of phosphorylated protein kinase B (Akt) and H3K36me3 in bones of NO66-TG mice, suggesting an inverse correlation between NO66 histone demethylase and the activity of IGF1R/Akt signaling. This correlation was further confirmed by in vitro assays of C2C12 cells with NO66 overexpression. We propose that the decrease in the IGF1R/Akt signaling pathway in mice with mesenchymal overexpression of NO66 may contribute in part to the inhibition of skeletal growth and bone formation.-Chen, Q., Zhang, L., de Crombrugghe, B., Krahe, R. Mesenchyme-specific overexpression of nucleolar protein 66 in mice inhibits skeletal growth and bone formation. FASEB J. 29, 2555-2565 (2015). www.fasebj.org Key Words: histone demethylase • transgenic mice • IGF1R/Akt signaling pathway • osterix THE MAJORITY OF THE MAMMALIAN skeleton is composed of 2 types of tissues: cartilage and bone. Cartilage is made by chondrocytes that are required for the longitudinal growth of bones. Bone forms through 2 distinct processes: intramembranous and endochondral ossification. In intramembranous ossification, bones form directly from the differentiation of mesenchymal progenitor cells, which then differentiate into cells of osteoblast lineage including preosteoblasts, osteoblasts, and osteocytes. However, in endochondral ossification, osteochondroprogenitors, which derive from mesenchymal progenitors, segregate into either chondrocytes that form a cartilage template or osteoblast precursors, which differentiate to form bone tissue that replaces the cartilage template. The progression through mesenchymal condensation, chondrocyte differentiation, and osteogenic-lineage commitment involves 3 key transcription factors: SRY-related HMG-box 9 (Sox9), runt-related transcription factor 2 (Runx2), and osterix (Osx). During endochondral ossification, Sox9 is required for mesenchymal progenitor condensation and expression of type II collagen (Col2) a1 (1-3). Runx2 has a dual role in the regulation of osteogenic-lineage commitment and the differentiation of mature chondrocytes (4-8). R...

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Growing Pains: The Need for Engineered Platforms to Study Growth Plate Biology

Tiffany

Harley

2022

Adv Healthcare Materials

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Growth plates, or physis, are highly specialized cartilage tissues responsible for longitudinal bone growth in children and adolescents. Chondrocytes that reside in growth plates are organized into three distinct zones essential for proper function. Modeling key features of growth plates may provide an avenue to develop advanced tissue engineering strategies and perspectives for cartilage and bone regenerative medicine applications and a platform to study processes linked to disease progression. In this review, a brief introduction of the growth plates and their role in skeletal development is first provided. Injuries and diseases of the growth plates as well as physiological and pathological mechanisms associated with remodeling and disease progression are discussed. Growth plate biology, namely, its architecture and extracellular matrix organization, resident cell types, and growth factor signaling are then focused. Next, opportunities and challenges for developing 3D biomaterial models to study aspects of growth plate biology and disease in vitro are discussed. Finally, opportunities for increasingly sophisticated in vitro biomaterial models of the growth plate to study spatiotemporal aspects of growth plate remodeling, to investigate multicellular signaling underlying growth plate biology, and to develop platforms that address key roadblocks to in vivo musculoskeletal tissue engineering applications are described.

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IGF-1R signaling in chondrocytes modulates growth plate development by interacting with the PTHrP/Ihh pathway

Cited by 113 publications

References 37 publications

IGF-1 regulation of key signaling pathways in bone

IGF-1 regulation of key signaling pathways in bone

Mesenchyme‐specific overexpression of nucleolar protein 66 in mice inhibits skeletal growth and bone formation

Growing Pains: The Need for Engineered Platforms to Study Growth Plate Biology

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