Human IGF-I propeptide A promotes articular chondrocyte biosynthesis and employs glycosylation-dependent heparin binding

Shi, Shuiliang; Kelly, Brian; Wang, Congrong; Klingler, Ken; Chan, Albert; Eckert, George J.; Trippel, Stephen B.

doi:10.1016/j.bbagen.2017.11.017

Cited by 8 publications

(4 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For skeletal muscle, the proform of IGF-IA, which retains the EA-peptide, as well as its N-glycosylated pro-IGF-IA constitute the largest proportion of IGF-I molecules stored in the tissue, and the EA peptide, regardless of its glycosylation, appears to enhance storage of IGF-I in the extracellular matrix (Durzynska et al, 2013a;Hede et al, 2012). Similarly, N-glycosylated pro-IGF-IA is also secreted by articular chondrocytes and binds tightly to heparin (Shi et al, 2018). Further, potency of IGF-IR activation is dependent upon the form of IGF-I, with relative activity of pro-IGF-I > mature IGF-I > glycosylated pro-IGF (Durzynska et al, 2013a).…”

Section: List Of Abbreviationsmentioning

confidence: 99%

Muscle insulin-like growth factor-I modulates murine craniofacial bone growth

Kok¹,

Crowder²,

Chee³

et al. 2021

eCM

View full text Add to dashboard Cite

Insulin-like growth factor I (IGF-I) is essential for muscle and bone development and a primary mediator of growth hormone (GH) actions. While studies have elucidated the importance of IGF-I specifically in muscle or bone development, few studies to date have evaluated the relationship between muscle and bone modulated by IGF-I in vivo, during post-natal growth. Mice with muscle-specific IGF-I overexpression (mIgf1+/+) were utilised to determine IGF-I- and muscle-mass-dependent effects on craniofacial skeleton development during post-natal growth. mIgf1+/+ mice displayed accelerated craniofacial bone growth when compared to wild-type animals. Virus-mediated expression of IGF-I targeting the masseter was performed to determine if post-natal modulation of IGF-I altered mandibular structures. Increased IGF-I in the masseter affected the mandibular base plane angle in a lateral manner, increasing the width of the mandible. At the cellular level, increased muscle IGF-I also accelerated cartilage thickness in the mandibular condyle. Importantly, mandibular length changes associated with increased IGF-I were not present in mice with genetic inhibition of muscle IGF-I receptor activity. These results demonstrated that muscle IGF-I could indirectly affect craniofacial growth through IGF-I-dependent increases in muscle hypertrophy. These findings have clinical implications when considering IGF-I as a therapeutic strategy for craniofacial disorders.

show abstract

Section: List Of Abbreviationsmentioning

confidence: 99%

Muscle insulin-like growth factor-I modulates murine craniofacial bone growth

Kok¹,

Crowder²,

Chee³

et al. 2021

eCM

View full text Add to dashboard Cite

show abstract

“…Recently, there have been some attempts of using the functional role of IGF1 precursor proteins in therapy of diseases affecting bone and cartilage [ 126 , 127 ]. Shi et al proved that the activity of pro-IGF1A, dependent on N-glycosylation at Asn92 in the EA peptide, determined heparin binding and caused an increase of biosynthesis in bovine articular chondrocytes.…”

Section: Igf1 Isoforms and Their Function In Major Body Tissuesmentioning

confidence: 99%

“…Shi et al proved that the activity of pro-IGF1A, dependent on N-glycosylation at Asn92 in the EA peptide, determined heparin binding and caused an increase of biosynthesis in bovine articular chondrocytes. This property could be used in therapy of cartilage damage caused by an injury or osteoarthritis [ 126 ]. A recent study on the rabbit bone injury model, using 52 different synthetic MGFs, proved that the T-MGF19E peptide can significantly promote osteoblastic MC3T3-E1 cells proliferation, differentiation, and mineralization, and thus promote bone injury healing [ 127 ].…”

Section: Igf1 Isoforms and Their Function In Major Body Tissuesmentioning

confidence: 99%

Role of Alternatively Spliced Messenger RNA (mRNA) Isoforms of the Insulin-Like Growth Factor 1 (IGF1) in Selected Human Tumors

Kasprzak

Szaflarski

2020

IJMS

View full text Add to dashboard Cite

Insulin-like growth factor 1 (IGF1) is a key regulator of tissue growth and development that is also implicated in the initiation and progression of various cancers. The human IGF1 gene contains six exons and five long introns, the transcription of which is controlled by two promoters (P1 and P2). Alternate promoter usage, as well as alternative splicing (AS) of IGF1, results in the expression of six various variants (isoforms) of mRNA, i.e., IA, IB, IC, IIA, IIB, and IIC. A mature 70-kDa IGF1 protein is coded only by exons 3 and 4, while exons 5 and 6 are alternatively spliced code for the three C-terminal E peptides: Ea (exon 6), Eb (exon 5), and Ec (fragments of exons 5 and 6). The most abundant of those transcripts is IGF1Ea, followed by IGF1Eb and IGF1Ec (also known as mechano-growth factor, MGF). The presence of different IGF1 transcripts suggests tissue-specific auto- and/or paracrine action, as well as separate regulation of both of these gene promoters. In physiology, the role of different IGF1 mRNA isoforms and pro-peptides is best recognized in skeletal muscle tissue. Their functions include the development and regeneration of muscles, as well as maintenance of proper muscle mass. In turn, in nervous tissue, a neuroprotective function of short peptides, produced as a result of IGF1 expression and characterized by significant blood-brain barrier penetrance, has been described and could be a potential therapeutic target. When it comes to the regulation of carcinogenesis, the potential biological role of different var iants of IGF1 mRNAs and pro-peptides is also intensively studied. This review highlights the role of IGF1 isoform expression (mRNAs, proteins) in physiology and different types of human tumors (e.g., breast cancer, cervical cancer, colorectal cancer, osteosarcoma, prostate and thyroid cancers), as well as mechanisms of IGF1 spliced variants involvement in tumor biology.

show abstract

“…Release of IGF‐I from the IGFBPs through protease activity is needed to enable receptor binding and activation. To date, it is not known if the longer IGF‐I forms also associate with IGFBPs, although previous work has demonstrated direct association of these forms with ECM 27,28 . Taken together, the regulation of IGF‐I production, stabilization, and activity occurs at many levels.…”

Section: Introductionmentioning

confidence: 99%

Ablation of specific insulin‐like growth factor I forms reveals the importance of cleavage for regenerative capacity and glycosylation for skeletal muscle storage

Luo,

Villani,

Lei

et al. 2024

The FASEB Journal

View full text Add to dashboard Cite

Insulin‐like growth factor‐I (IGF‐I) facilitates mitotic and anabolic actions in all tissues. In skeletal muscle, IGF‐I can promote growth and resolution of damage by promoting satellite cell proliferation and differentiation, suppressing inflammation, and enhancing fiber formation. While the most well‐characterized form of IGF‐I is the mature protein, alternative splicing and post‐translational modification complexity lead to several additional forms of IGF‐I. Previous studies showed muscle efficiently stores glycosylated pro‐IGF‐I. However, non‐glycosylated forms display more efficient IGF‐I receptor activation in vitro, suggesting that the removal of the glycosylated C terminus is a necessary step to enable increased activity. We employed CRISPR‐Cas9 gene editing to ablate IGF‐I glycosylation sites (2ND) or its cleavage site (3RA) in mice to determine the necessity of glycosylation or cleavage for IGF‐I function in postnatal growth and during muscle regeneration. 3RA mice had the highest circulating and muscle IGF‐I content, whereas 2ND mice had the lowest levels compared to wild‐type mice. After weaning, 4‐week‐old 2ND mice exhibited higher body and skeletal muscle mass than other strains. However, by 16 weeks of age, muscle and body size differences disappeared. Even though 3RA mice had more IGF‐I stored in muscle in homeostatic conditions, regeneration was delayed after cardiotoxin‐induced injury, with prolonged necrosis most evident at 5 days post injury (dpi). In contrast, 2ND displayed improved regeneration with reduced necrosis, and greater fiber size and muscle mass at 11 and 21 dpi. Overall, these results demonstrate that while IGF‐I glycosylation may be important for storage, cleavage is needed to enable IGF‐I to be used for efficient activity in postnatal growth and following acute injury.

show abstract

Human IGF-I propeptide A promotes articular chondrocyte biosynthesis and employs glycosylation-dependent heparin binding

Abstract: These data identify human pro-insulin-like growth factor IA as a bifunctional protein. Its combined ability to bind heparin and augment chondrocyte biosynthesis makes it a promising therapeutic agent for cartilage damage due to trauma and osteoarthritis.

Cited by 8 publications

References 45 publications

Muscle insulin-like growth factor-I modulates murine craniofacial bone growth

Muscle insulin-like growth factor-I modulates murine craniofacial bone growth

Role of Alternatively Spliced Messenger RNA (mRNA) Isoforms of the Insulin-Like Growth Factor 1 (IGF1) in Selected Human Tumors

Ablation of specific insulin‐like growth factor I forms reveals the importance of cleavage for regenerative capacity and glycosylation for skeletal muscle storage

Contact Info

Product

Resources

About