2. Academic Validation
  3. HYAL2-generated low-molecular-weight hyaluronic acid promotes intervertebral disc degeneration via the CD44/AKT signaling axis

HYAL2-generated low-molecular-weight hyaluronic acid promotes intervertebral disc degeneration via the CD44/AKT signaling axis

  • Biochem Biophys Res Commun. 2026 Apr 30:811:153576. doi: 10.1016/j.bbrc.2026.153576.
Shatong He 1,  Jinquan Ma 1,  Chao Yao 1,  Yang Ye 1,  Chen Yang 1,  Zeng Xu 1,  Fazhi Zang 2,  Jie Zhou 3,  Huajiang Chen 4
Affiliations

Affiliations

  • 1 Department of Orthopedics, The Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China.
  • 2 Department of Orthopedics, The Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China. Electronic address: [email protected].
  • 3 Department of Orthopedics, Pudong New Area People's Hospital, 490 Chuanhuan South Road, Shanghai, 201299, China.
  • 4 Department of Orthopedics, The Second Affiliated Hospital of Naval Medical University, Shanghai, 200003, China. Electronic address: [email protected].
PMID: 41806573 DOI: 10.1016/j.bbrc.2026.153576
Abstract

Intervertebral disc degeneration (IVDD) is a major cause of low back pain. Hyaluronic acid (HA), a key component of the extracellular matrix (ECM), has an essential yet complex role in IVDD, and the balance between its high-molecular-weight (HMW) and low-molecular-weight (LMW) forms appears to be critical. Here, we identify hyaluronidase 2 (HYAL2) and its principal catalytic product, LMW-HA, as active drivers of IVDD. HYAL2 expression was markedly increased in degenerative discs in a mouse IVDD model, and genetic ablation of HYAL2 attenuated disease progression, indicating a pathogenic contribution. In vitro, HYAL2 overexpression and exogenous LMW-HA both induced nucleus pulposus (NP) cell senescence, inflammatory activation and ECM degradation. Mechanistically, we identify CD44 as the essential receptor mediating these effects: engagement of CD44 by LMW-HA suppressed Akt phosphorylation, whereas CD44 knockdown abolished LMW-HA-induced Akt inactivation and NP cell degeneration. Conversely, Akt reactivation reversed the deleterious cellular phenotypes. Collectively, these data define the HYAL2/LMW-HA/CD44/Akt axis as a central pathogenic pathway in IVDD and suggest several potential targets for disease-modifying interventions.

Keywords

CD44; HYAL2; IVDD; LMW-HA; SASP; Senescence.

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