Conditional Deletion of HIF-2α in Mouse Nucleus Pulposus Reduces Fibrosis and Provides Mild and Transient Protection From Age-Dependent Structural Changes in Intervertebral Disc

Johnston, Shira N; Madhu, Vedavathi; Shapiro, Irving M.; Risbud, Makarand V.

doi:10.1002/jbmr.4707

Cited by 10 publications

(33 citation statements)

References 88 publications

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“…Moreover, exogenous expression of HIF-1-α limits disc degeneration and reduces apoptosis of nucleus pulposus cells in a murine disc injury model [ 163 ]. Likewise, conditional deletion of HIF-2-α limits age-dependent changes within the IVD [ 164 ]. There are a few reports showing that hypoxia impacts the response of nucleus pulposus cells to macrophage-produced inflammatory cytokines.…”

Section: Molecular Control Of Macrophage Function During Ivd Degenera...mentioning

confidence: 99%

Macrophages and Intervertebral Disc Degeneration

Koroth

Buko

Abbott

et al. 2023

IJMS

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The intervertebral disc (IVD) aids in motion and acts to absorb energy transmitted to the spine. With little inherent regenerative capacity, degeneration of the intervertebral disc results in intervertebral disc disease, which contributes to low back pain and significant disability in many individuals. Increasing evidence suggests that IVD degeneration is a disease of the whole joint that is associated with significant inflammation. Moreover, studies show elevated macrophage accumulation within the IVD with increasing levels of disease severity; however, we still need to understand the roles, be they causative or consequential, of macrophages during the degenerative process. In this narrative review, we discuss hallmarks of IVD degeneration, showcase evidence of macrophage involvement during disc degeneration, and explore burgeoning research aimed at understanding the molecular pathways regulating macrophage functions during intervertebral disc degeneration.

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Section: Molecular Control Of Macrophage Function During Ivd Degenera...mentioning

confidence: 99%

Macrophages and Intervertebral Disc Degeneration

Koroth

Buko

Abbott

et al. 2023

IJMS

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“…Following Safranin-O/Fast Green/Hematoxylin staining, images were acquired on a light microscope (Axio Imager 2; Carl Zeiss Microscopy) using 5x/0.15 N-Achroplan (Carl Zeiss) objective and Zen2™ software (Carl Zeiss). The health of disc compartments was assessed by at least four blinded graders using Modified Thompson Grading (56,(58)(59)(60)(61). Picrosirius red staining (Polysciences, 24901) was performed to assess collagen fibril thickness, and images were acquired using 4x /0.25 Pol /WD 7.0 (Nikon) objective on a polarizing light microscope (Eclipse LV100 POL; Nikon).…”

Section: Histological Analysismentioning

confidence: 99%

“…Raw spectra went through an atmospheric correction and converted to second derivative spectra to resolve underlying peaks and corrected for baseline offsets. Savitsky-Golay smoothing (filter order of 3 and filter length of 9) was applied, and spectra inverted by multiplication by -1 to convert to positive peak heights as appropriate (56,60). Mean second-derivative absorbances in the amide I (1660 cm -1 ), amide II (1549 cm -1 ), collagen side chain vibration (1338 cm -1 ), and sulfated proteoglycan sugar ring (1064 cm -1 ) peaks were quantified and compared in the NP and AF compartments.…”

Section: Histological Analysismentioning

confidence: 99%

SDC4 deletion perturbs intervertebral disc matrix homeostasis and promotes early osteopenia in the aging spine

Sao,

Risbud

2023

Preprint

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Syndecan 4 (SDC4), a cell surface heparan sulfate proteoglycan, is known to regulate matrix catabolism by nucleus pulposus cells in an inflammatory milieu. However, the role of SDC4 in the aging spine has never been explored. Here we analyzed the spinal phenotype of SDC4 global knockout (KO) mice as a function of age. Micro computed tomography showed that SDC4 deletion severely reduced vertebral trabecular and cortical bone mass, and biomechanical properties of vertebrae were significantly altered in SDC4 KO mice. These changes in vertebral bone were due to elevated osteoclastic activity in KO mice. The histological assessment also showed subtle phenotypic changes in the intervertebral discs. Imaging-Fourier transform-infrared (FTIR) analyses showed a reduced relative ratio of mature collagen crosslink in young adult NP and AF compartments of KO compared to wildtype (WT) mice. Additionally, relative chondroitin sulfated glycosaminoglycan (GAG) levels increased in the NP compartment of the KO mice. Transcriptomic analysis of NP tissue using CompBio, an AI-based tool showed biological themes associated with prominent dysregulation of heparan sulfate GAG degradation, mitochondria metabolism, autophagy, and endoplasmic reticulum to Golgi protein processing. Overall, this study highlights the important role of SDC4 in fine-tuning vertebral bone homeostasis and extracellular matrix homeostasis in the intervertebral disc.

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“…A broader categorization of their functions shows that HIF-1α primarily controls cell metabolic activities, whereas HIF-2α regulates cell proliferation, survival, extracellular matrix homeostasis, and oxidative defenses (9). While both HIF-α isoforms are robustly expressed in the NP, HIF-1α is the critical driver of glycolysis, energetics, and overall survival of cells within the specialized niche of the disc (11–14). Notochord-specific FoxA2 Cre ; HIF-1 α mice show a prominent NP cell apoptosis by birth and subsequently, the NP tissue is replaced by cartilage-like tissue, highlighting the central role of HIF-1α in survival and adaptation of NP cells (15).…”

Section: Introductionmentioning

confidence: 99%

“…Noteworthy, in contrast to the dramatic phenotype of HIF-1α FoxA2Cre mice, our recent investigations pointed to a different function of HIF-2α in the intervertebral disc. HIF-2 α FoxA2Cre mice did not result in early cell death, but showed mild and transient protection against age-dependent intervertebral disc degeneration characterized by reduced NP tissue fibrosis (14). While these investigations implied a pro-pathogenic role of HIF-2α in the disc, little is known about the consequences of elevated HIF-2α activity in the NP compartment and its impact on overall intervertebral disc health.…”

Section: Introductionmentioning

confidence: 99%

Increased HIF-2α Activity in the Nucleus Pulposus Causes Intervertebral Disc Degeneration in the Aging Mouse Spine

Johnston,

Tsingas,

Ain

et al. 2023

Preprint

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Hypoxia-inducible factors (HIFs) are essential to the homeostasis of hypoxic tissues. Although HIF-2α, is expressed in nucleus pulposus (NP) cells, consequences of elevated HIF-2 activity on disc health remains unknown. We expressed HIF-2α with proline to alanine substitutions (P405A;P531A) in the Oxygen-dependent degradation domain (HIF-2αdPA) in the NP tissue using an inducible, nucleus pulposus-specific K19CreERTallele to study HIF-2α function in the adult intervertebral disc. Expression of HIF-2α in NP impacted disc morphology, as evident from small but significantly higher scores of degeneration in NP of 24-month-old K19CreERT; HIF-2αdPA(K19-dPA) mice. Noteworthy, comparisons of grades within each genotype between 14 months and 24 months indicated that HIF-2α overexpression contributed to more pronounced changes than aging alone. The annulus fibrosus (AF) compartment in the 14-month-old K19-dPA mice exhibited lower collagen turnover and Fourier transform-infrared (FTIR) spectroscopic imaging analyses showed changes in the biochemical composition of the 14-and 24-month-old K19-dPA mice. Moreover, there were changes in aggrecan, chondroitin sulfate, and COMP abundance without alterations in NP phenotypic marker CA3, suggesting the overexpression of HIF-2α had some impact on matrix composition but not the cell phenotype. Mechanistically, the global transcriptomic analysis showed enrichment of differentially expressed genes in themes closely related to NP cell function such as cilia, SLIT/ROBO pathway, and HIF/Hypoxia signaling at both 14- and 24-months. Together, these findings underscore the role of HIF-2α in the pathogenesis of disc degeneration in the aged spine.

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Conditional Deletion of HIF-2α in Mouse Nucleus Pulposus Reduces Fibrosis and Provides Mild and Transient Protection From Age-Dependent Structural Changes in Intervertebral Disc

Cited by 10 publications

References 88 publications

Macrophages and Intervertebral Disc Degeneration

Macrophages and Intervertebral Disc Degeneration

SDC4 deletion perturbs intervertebral disc matrix homeostasis and promotes early osteopenia in the aging spine

Increased HIF-2α Activity in the Nucleus Pulposus Causes Intervertebral Disc Degeneration in the Aging Mouse Spine

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