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Effects of suppressing bioavailability of insulin-like growth factor on age-associated intervertebral disc degeneration.

ABSTRACT: Suppression of the insulin-like growth factor-1 (IGF-1) signaling pathway reduces age-related disorders and increases lifespan across species, making the IGF-1 pathway a key regulator of aging. Previous in vitro intervertebral disc cell studies have reported the pro-anabolic effect of exogenously adding IGF-1 on matrix production. However, the overall effects of suppressing IGF-1 signaling on age-related intervertebral disc degeneration (IDD) is not known. Here, the effects of suppressing IGF-1 signaling on age-related IDD in vivo were examined using PAPPA ^-/- mice. These are animals with targeted deletion of pregnancy-associated plasma protein A (PAPPA), the major protease that cleaves inhibitory IGF binding proteins that control bioavailability of IGF-1 for cell signaling. Compared to age-matched wild-type (Wt) littermates, reduced levels of matrix proteoglycan (PG) and aggrecan were seen in discs of 23-month old PAPPA ^-/- mice. Decreased aggrecanolysis and expression of two key catabolic markers, matrix metalloproteinase-3 and a disintegrin and metalloproteinase with thrombospondin motifs-4, were also observed in discs of old PAPPA ^-/- mice compared to Wt littermates. Suppressing IGF-1 signaling has been implicated to shift cellular metabolism toward maintenance rather than growth and decreasing cellular senescence. Along this line, discs of old PAPPA ^-/- mice also exhibited lower cellular senescence, assessed by p53 and lamin B1 markers. Collectively, the data reveal complex regulation of disc matrix homeostasis by PAPPA/IGF-1 signaling during chronologic aging, that is, reduced IGF-1 bioavailability confers the benefit of decreasing disc cellular senescence and matrix catabolism but also the disadvantage of decreasing disc PG matrix anabolism. This pathway requires further mechanistic elucidation before IGF-1 could be considered as a therapeutic growth factor for treating IDD.

SUBMITTER: Kritschil R

PROVIDER: S-EPMC7770198 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Effects of suppressing bioavailability of insulin-like growth factor on age-associated intervertebral disc degeneration.

Kritschil Rebecca R Zhang Zhongying Z Lei Changbin C Zhong Jiongbiao J Dong Qing Q Lee Joon J Conover Cheryl A CA Sowa Gwendolyn G Vallejo Abbe N AN Vo Nam N

JOR spine 20200727 4

Suppression of the insulin-like growth factor-1 (IGF-1) signaling pathway reduces age-related disorders and increases lifespan across species, making the IGF-1 pathway a key regulator of aging. Previous in vitro intervertebral disc cell studies have reported the pro-anabolic effect of exogenously adding IGF-1 on matrix production. However, the overall effects of suppressing IGF-1 signaling on age-related intervertebral disc degeneration (IDD) is not known. Here, the effects of suppressing IGF-1 ...[more]

PMID: 33392450

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Project description:Fibroblast growth factor 18 (FGF-18) is a well-characterized anabolic growth factor involved in cartilage homeostasis. However, the effect of FGF-18 on intervertebral disc (IVD) degeneration has not been investigated. The present study aimed to investigate the role of FGF-18 in the process of rabbit IVD degeneration. In vitro, primary nucleus pulposus cells (NPs) were cultured and transfected with a lentivirus. Tert-butyl hydroperoxide (TBHP) was used to induce apoptosis in NPs on the second passage, while overexpression of FGF-18 in NPs attenuated TBHP-induced apoptosis. A rabbit annular puncture model was generated to induce IVD degeneration in vivo. The discs were injected with an FGF-18-overexpression lentivirus or a negative control lentivirus. In the sham group, the discs were exposed and not punctured. Disc degeneration was evaluated using H&E staining and a histological grading system. Reverse transcription-quantitative PCR was used to detect the expression of the extracellular matrix-degrading enzymes matrix metalloproteinase-3 (MMP-3) and A disintegrin and metalloproteinase with thrombospondin motifs 5 (ADAMTS-5). Nucleus pulposus apoptosis was detected via western blotting, immunohistochemical methods and TUNEL staining. Histologic examination showed that disc degeneration was attenuated after FGF-18 overexpression treatment. At 8 weeks after surgery, the expression of MMP-3 and ADAMTS-5 in the annular puncture groups was higher compared with in the sham group. FGF-18 treatment inhibited the expression of MMP-3 and ADAMTS-5 at the mRNA level. Western blot assays indicated that the expression level of Bax was significantly reduced in the FGF-18 groups, and that the expression level of Bcl-2 was significantly increased compared with those in the control group. Moreover, immunohistochemical analysis indicated that the FGF-18 group exhibited a lower percentage of cleaved caspase 3-positive NPs. Quantification of the TUNEL staining demonstrated that the FGF-18 group had fewer apoptotic NPs than the control group. These findings indicated that FGF-18 could delay IVD degeneration by inhibiting the apoptosis of NPs and the expression of matrix-degrading enzymes.

Project description:The distribution of bone tissue within the vertebra can modulate vertebral strength independently of average density and may change with age and disc degeneration. Our results show that the age-associated decrease in bone density is spatially non-uniform and associated with disc health, suggesting a mechanistic interplay between disc and vertebra. PURPOSE:While the decline of bone mineral density (BMD) in the aging spine is well established, the extent to which age influences BMD distribution within the vertebra is less clear. Measures of regional BMD (rBMD) may improve predictions of vertebral strength and suggest how vertebrae might adapt with intervertebral disc degeneration. Thus, we aimed to assess how rBMD values were associated with age, sex, and disc height loss (DHL). METHODS:We measured rBMD in the L3 vertebra of 377 participants from the Framingham Heart Study (41-83 years, 181 M/196 F). Integral (Int.BMD) and trabecular BMD (Tb.BMD) were measured from QCT images. rBMD ratios (anterior/posterior, superior/mid-transverse, inferior/mid-transverse, and central/outer) were calculated from the centrum. A radiologist assigned a DHL severity score to adjacent intervertebral discs (L2-L3 and L3-L4). RESULTS:Int.BMD and Tb.BMD were both associated with age, though the decrease across age was greater in women (Int.BMD, -?2.6 mg/cm3 per year; Tb.BMD, -?2.6 mg/cm3 per year) than men (Int.BMD, -?0.5 mg/cm3 per year; Tb.BMD, -?1.2 mg/cm3 per year). The central/outer (-?0.027/decade) and superior/mid-transverse (-?0.018/decade) rBMD ratios were negatively associated with age, with similar trends in men and women. Higher Int.BMD or Tb.BMD was associated with increased odds of DHL after adjusting for age and sex. Low central/outer ratio and high anterior/poster and superior/mid-transverse ratios were also associated with increased odds of DHL. CONCLUSIONS:Our results indicate that the distribution of bone within the L3 vertebra is different across age, but not between sexes, and is associated with disc degeneration.

Dataset Information

Effects of suppressing bioavailability of insulin-like growth factor on age-associated intervertebral disc degeneration.

Publications

Effects of suppressing bioavailability of insulin-like growth factor on age-associated intervertebral disc degeneration.

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