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Background <p>Fetuin-A is a glycoprotein with high affinity for calcium-phosphates, with a role in cartilage and bone metabolism, and an anti-inflammatory role in injury. Studies have shown decreasing serum fetuin-A levels in patients with severe osteoarthritis (OA), and lower amounts of fetuin-A in OA sclerotic osteoblasts. Therefore, decreasing fetuin-A during OA might be responsible for increased inflammation, cartilage mineralization and subchondral bone thickness. To assess the therapeutic potential of fetuin-A in post-traumatic OA (PTOA), we used micrometric hyaluronic-acid particles (µHA) to achieve a sustained intra-articular release of fetuin-A into diseased joint knees and followed PTOA progression over time. Because OA progression may lead to muscle degeneration, we also assessed muscle strength.</p> Methods <p>Shape-defined hyaluronic-acid microparticles were fabricated and associated with fetuin-A, generating a fetuin-A µHA complex (Fet-µHA). After physicochemical characterization and biocompatibility studies on chondrocytes, the release profile of fetuin-A from Fet-µHA was established. The therapeutic efficacy of Fet-µHA on PTOA was assessed using the destabilization of the medial meniscus (DMM) model. We intra-articularly injected Fet-µHA (20&#xa0;mg/kg, every 3wks), empty-µHA, or saline into DMM knees of C57BL/6&#xa0;J mice, following OA outcomes at early and severe PTOA (4&#xa0;weeks and 12&#xa0;weeks post-DMM). Outcomes included cartilage structure (ACS score, H&amp;E), matrix loss (Safranin-O score), articular cartilage (AC) thinning, osteophyte development, bone histomorphometry, synovial hyperplasia and maximal tetanic force. All group analyses were performed with ordinary two-way ANOVA (cell viability) or one-way ANOVA (in vivo studies), followed by Tukey’s post-hoc test for multiple comparisons (statistical significance at <i>P</i> &lt; 0.05).</p> Results <p>The in vitro studies confirmed the biocompatibility of Fet-µHA and established a release profile up to 45&#xa0;days. In vivo intra-articular administration of the Fet-µHA into DMM knees was beneficial for OA cartilage,bone damage and synovial hyperplasia. Furthermore, Fet-µHA treatment led to a significative improvement of tetanic max contraction force at the severe stage.</p> Conclusions <p>This pre-clinical study not only opens new perspectives for the potential use of fetuin-A in OA treatment but confirms µHA as a promising drug carrier in OA.</p>

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Sustained release of exogeneous fetuin-A from Hyaluronic acid microplates decreases joint degeneration, synovial hyperplasia and muscle damage in a murine post-traumatic osteoarthritis model

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年9月25日

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  • Helen Willcockson,
  • Antonietta Greco,
  • Agnese Fragassi,
  • Roberto Palomba,
  • Kihyun Kwon,
  • Huseyin Ozkan,
  • Samuel T. Bartlett,
  • Richard F. Loeser,
  • Paolo Decuzzi,
  • Lara Longobardi

摘要

Background

Fetuin-A is a glycoprotein with high affinity for calcium-phosphates, with a role in cartilage and bone metabolism, and an anti-inflammatory role in injury. Studies have shown decreasing serum fetuin-A levels in patients with severe osteoarthritis (OA), and lower amounts of fetuin-A in OA sclerotic osteoblasts. Therefore, decreasing fetuin-A during OA might be responsible for increased inflammation, cartilage mineralization and subchondral bone thickness. To assess the therapeutic potential of fetuin-A in post-traumatic OA (PTOA), we used micrometric hyaluronic-acid particles (µHA) to achieve a sustained intra-articular release of fetuin-A into diseased joint knees and followed PTOA progression over time. Because OA progression may lead to muscle degeneration, we also assessed muscle strength.

Methods

Shape-defined hyaluronic-acid microparticles were fabricated and associated with fetuin-A, generating a fetuin-A µHA complex (Fet-µHA). After physicochemical characterization and biocompatibility studies on chondrocytes, the release profile of fetuin-A from Fet-µHA was established. The therapeutic efficacy of Fet-µHA on PTOA was assessed using the destabilization of the medial meniscus (DMM) model. We intra-articularly injected Fet-µHA (20 mg/kg, every 3wks), empty-µHA, or saline into DMM knees of C57BL/6 J mice, following OA outcomes at early and severe PTOA (4 weeks and 12 weeks post-DMM). Outcomes included cartilage structure (ACS score, H&E), matrix loss (Safranin-O score), articular cartilage (AC) thinning, osteophyte development, bone histomorphometry, synovial hyperplasia and maximal tetanic force. All group analyses were performed with ordinary two-way ANOVA (cell viability) or one-way ANOVA (in vivo studies), followed by Tukey’s post-hoc test for multiple comparisons (statistical significance at P < 0.05).

Results

The in vitro studies confirmed the biocompatibility of Fet-µHA and established a release profile up to 45 days. In vivo intra-articular administration of the Fet-µHA into DMM knees was beneficial for OA cartilage,bone damage and synovial hyperplasia. Furthermore, Fet-µHA treatment led to a significative improvement of tetanic max contraction force at the severe stage.

Conclusions

This pre-clinical study not only opens new perspectives for the potential use of fetuin-A in OA treatment but confirms µHA as a promising drug carrier in OA.