# Altered nicotinamide adenine dinucleotide metabolism drives cartilage degeneration and osteoarthritis

## TL;DR

This study shows that low NAD+ levels in cartilage, caused by increased PARP14 activity, contribute to osteoarthritis, and boosting NAD+ can help prevent cartilage damage.

## Contribution

The study identifies PARP14 as a key driver of NAD+ depletion in osteoarthritis and shows that NAD+ augmentation can protect cartilage.

## Key findings

- PARP14 is upregulated in OA cartilage and contributes to NAD+ depletion.
- NAD+ precursor treatment and NMNAT1 overexpression protect against cartilage degeneration in OA models.
- PARP14 silencing restores NAD+ levels and reduces OA-related matrix degradation.

## Abstract

We previously conducted a comprehensive survey of energy metabolism in osteoarthritis (OA), revealing significant reductions of nicotinamide adenine dinucleotide (NAD+) levels in OA cartilage. This study aimed to test whether NAD+ deficiency present in OA plays a mechanistic role in disease development.

We conducted integrative analyses across human, murine, and rat OA models to examine NAD⁺ metabolism and its regulatory enzymes. The impact of pharmacological NAD⁺ augmentation (via nicotinamide mononucleotide (NMN) and nicotinamide riboside (NR)) and genetic overexpression of the NAD⁺ biosynthetic enzyme NMN adenosyltransferase (NMNAT1) was tested in surgical and aging‐related OA models. Expression and function of the NAD⁺‐consuming enzyme poly (ADP‐ribose) polymerase 14 (PARP14) were examined via siRNA knockdown in chondrocytes under inflammatory conditions, coupled with metabolic assays and extracellular matrix gene profiling.

NAD+ levels were decreased in human and murine OA, accompanied by upregulation of both the NAD+ biosynthetic enzyme Nicotinamide phosphoribosyltransferase (NAMPT) and the NAD+ consuming enzyme PARP14. While NAMPT expression was elevated, its effect on total NAD⁺ may be offset by increased NAD⁺ consumption or substrate limitation under inflammatory conditions. Treatment with NAD+ precursors and transgenic overexpression of NMNAT1 suppressed cartilage disruption during in aging murine and surgical rat model of OA. Increased expression of PARP14 in OA cartilage contributed to NAD+ decline and promoted cartilage degeneration.

This study reveals that dysregulated NAD⁺ metabolism, driven by increased PARP14 consumption, constitutes a potential mechanism underlying OA pathogenesis. Our findings support the concept that enhancing NAD⁺ availability via precursors or biosynthetic pathway modulation may offer disease‐modifying effects at the molecular and histological level. Further investigation is needed to determine the functional and translational implications of targeting this pathway.

PARP14 is upregulated in OA cartilage and contributes to NAD⁺ depletion.PARP14 silencing restores NAD⁺ levels and represses OA‐related metabolic and matrix‐degrading changes.NAD⁺ precursor treatment and NMNAT1 overexpression protect against cartilage degeneration in aging and post‐traumatic OA models.

PARP14 is upregulated in OA cartilage and contributes to NAD⁺ depletion.

PARP14 silencing restores NAD⁺ levels and represses OA‐related metabolic and matrix‐degrading changes.

NAD⁺ precursor treatment and NMNAT1 overexpression protect against cartilage degeneration in aging and post‐traumatic OA models.

PARP14 is upregulated in OA cartilage and contributes to NAD⁺ depletion.

PARP14 silencing restores NAD⁺ levels and represses OA‐related metabolic and matrix‐degrading changes.

NAD⁺ precursor treatment and NMNAT1 overexpression protect against cartilage degeneration in aging and post‐traumatic OA models.