Human osteocyte expression of Nerve Growth Factor: The effect of Pentosan Polysulphate Sodium (PPS) and implications for pain associated with knee osteoarthritis

PLoS One. 2019 Sep 26;14(9):e0222602. doi: 10.1371/journal.pone.0222602. eCollection 2019.


Pentosan polysulphate sodium (PPS) is a promising therapeutic agent for blocking knee pain in individuals with knee osteoarthritis (KOA). The mode of action of PPS in this context is unknown. We hypothesised that the osteocyte, being the principal cell type in the sub-chondral bone, was capable of expressing the pain mediator Nerve Growth Factor (NGF), and that this may be altered in the presence of PPS. We tested the expression of NGF and the response to PPS in the presence or absence of the proinflammatory cytokine tumour necrosis factor-alpha (TNFα), in human osteocytes. For this we differentiated human primary osteoblasts grown from subchondral bone obtained at primary knee arthroplasty for KOA to an osteocyte-like stage over 28d. We also tested NGF expression in fresh osteocytes obtained by sequential digestion from KOA bone and by immunofluorescence in KOA bone sections. We demonstrate for the first time the production and secretion of NGF/proNGF by this cell type derived from patients with KOA, implicating osteocytes in the pain response in this pathological condition and possibly others. PPS inhibited TNFα-induced levels of proNGF secretion and TNFα induced NGF mRNA expression. Together, this provides evidence that PPS may act to suppress the release of NGF in the subchondral bone to ameliorate pain associated with knee osteoarthritis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aged
  • Arthralgia / drug therapy*
  • Arthralgia / etiology
  • Female
  • Humans
  • Nerve Growth Factor / metabolism*
  • Osteoarthritis, Knee / complications
  • Osteoarthritis, Knee / drug therapy*
  • Osteocytes / drug effects
  • Osteocytes / metabolism*
  • Pentosan Sulfuric Polyester / pharmacology*
  • Transcriptome / drug effects
  • Tumor Necrosis Factor-alpha / pharmacology


  • Tumor Necrosis Factor-alpha
  • Pentosan Sulfuric Polyester
  • Nerve Growth Factor

Grants and funding

This study was funded by a research grant from Paradigm Biopharmaceuticals Ltd ( and from a Project Grant awarded to GJA from the National Health and Medical Research Council of Australia (NHMRC) (Project ID1106029). CJMS was supported by an Australian Postgraduate Award scholarship. GJA is an NHMRC Senior Research Fellow. Paradigm Biopharmaceuticals Ltd provided additional funding in the form of salary to RK. The specific roles of these authors are articulated in the ‘author contributions’ section. The funders did not have any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript beyond those specified.