SHH-dependent knockout of HIF-1 alpha accelerates the degenerative process in mouse intervertebral disc

Area of Science:

• Biochemistry
• Cell Biology
• Orthopedics

Background:

• Hypoxia-inducible factor-1alpha (HIF-1alpha) is implicated in nucleus pulposus cell (NPC) metabolism and extracellular matrix synthesis.
• HIF-1alpha is suspected to play a role in intervertebral disc degeneration (IVDD).

Purpose of the Study:

• To investigate the role of HIF-1alpha in disc degeneration in vivo.
• To utilize a conditional HIF-1alpha knockout (KO) mouse model for this investigation.

Main Methods:

• Generated conditional HIF-1alpha KO mice (HIF-1alpha fl/fl-ShhCre+).
• Harvested and analyzed lumbar disc samples from wild-type and KO mice at various ages (3 days, 6, 12 weeks).
• Employed in situ hybridization, immunohistochemistry, and histological grading (Boos et al. classification) to assess knockout efficacy, NPC death, degeneration, and expression of aggrecan, type-II collagen, and VEGF.

Main Results:

• HIF-1alpha KO mice exhibited increased NPC death and significant signs of disc degeneration compared to wild-type mice at 6 and 12 weeks.
• Reduced expression of aggrecan, type-II collagen, and VEGF was observed in the intervertebral discs of HIF-1alpha KO mice.
• Degeneration scores were significantly higher in HIF-1alpha KO mice.

Conclusions:

• HIF-1alpha is essential for NPC survival and maintaining extracellular matrix homeostasis.
• The HIF-1alpha/VEGF signaling pathway is critical for these functions.
• HIF-1alpha plays a pivotal role in preventing the development of intervertebral disc degeneration.