Intervertebral disc degeneration is accelerated by GH overexpression but attenuated by GH antagonism

Background: Intervertebral disc degeneration (IVDD) is a leading contributor to lower back pain, yet its underlying mechanisms remain poorly defined. While insulin-like growth factor 1 (IGF-1) has been implicated in disc homeostasis, the specific contributions of growth hormone (GH)—a key upstream regulator of IGF-1 that also acts and independently influences skeletal tissues—have not been thoroughly investigated in the context of IVDD. Methods: We utilized transgenic mouse models with altered GH signaling, including bovine GH (bGH)-expressing and GH receptor antagonist (GHA) mice, to investigate how GH excess or GH antagonism influences disc structure, degeneration, and to identify potential molecular pathways involved in disc maintenance and degradation. Disc histology was evaluated using Safranin-O/Fast Green staining and quantitative scoring across the nucleus pulposus (NP), annulus fibrosus (AF), and endplate (EP) compartments. Bulk RNA sequencing was conducted on intervertebral discs harvested from 12-month-old bovine GH-overexpressing (bGH) and wild-type (WT) mice to identify transcriptional changes associated with GH overexpression. Results: bGH mice developed visible IVDD as early as 3 months of age, with degenerative features across all disc compartments. At 15 months, bGH males exhibited more severe degeneration than females, including greater proteoglycan loss, disc height reduction, and fibrotic remodeling. In contrast, 2-year-old GHA mice were protected from age-related disc degeneration, maintaining disc integrity and low histological scores. Transcriptomic analysis revealed sex-specific upregulation of inflammatory and catabolic pathways in bGH discs, including TNF, IL-17, and NOD-like receptor signaling, alongside downregulation of anabolic and ECM maintenance pathways such as PI3K-Akt and mTOR. Notably, these effects were more pronounced in males than females. Conclusion: Abundance of GH accelerates IVDD through sex-dependent activation of inflammatory and matrix-degrading pathways, while GH antagonism confers protection against age associated disc degeneration. These findings identify GH as a critical regulator of disc homeostasis and a potential therapeutic target for mitigating IVDD and associated low back pain.