In‐Vivo Efficacy of Recombinant Human Hyaluronidase (rHuPH20) Injection for Accelerated Healing of Murine Retrocalcaneal Bursitis and Tendinopathy

Abstract

The deposition of aggrecan/hyaluronan (HA)‐rich matrix within the tendon body and surrounding peritenon impede tendon healing and result in compromised biomechanical properties. Hence, the development of novel strategies to achieve targeted removal of the aggrecan‐HA pericellular matrix may be effective in treating tendinopathy. The current study examined the therapeutic potential of a recombinant human hyaluronidase, rHuPH20 (FDA approved for reducing HA accumulation in tumors) for treating murine Achilles tendinopathy. The 12‐week‐old C57Bl/6 male mice were injected with two doses of rHuTGF‐β1 into the retrocalcaneal bursa (RCB) to induce a combined bursitis and tendinopathy. Twenty‐four hours following induction of injury, treatment groups were administered rHuPH20 Hyaluronidase (rHuPH20; Halozyme Therapeutics) into the RCB. At either 6 h (acute), 9 days, or 25 days following hyaluronidase treatment, Achilles tendons were analyzed for gene expression, histology and immunohistochemistry, fluorophore‐assisted carbohydrate electrophoresis, and biomechanical properties. The rHuPH20 treatment was effective, particularly at the acute and 9‐day time points, in (a) removing HA deposits from the Achilles tendon and surrounding tissues, (b) improving biomechanical properties of the healing tendon, and (c) eliciting targeted increases in expression of specific cell fate, extracellular matrix metabolism, and inflammatory genes. The potential of rHuPH20 to effectively clear the pro‐inflammatory, HA‐rich matrix within the RCB and tendon strongly supports the future refinement of injectable glycosidase preparations as potential treatments to protect or regenerate tendon tissue by reducing inflammation and scarring in the presence of bursitis or other inducers of damage such as mechanical overuse. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:59–69, 2020

Exploring the role of intratendinous pressure in the pathogenesis of tendon pathology: a narrative review and conceptual framework

“…The use of human recombinant hyaluronidase may therefore be particularly useful in the reactive or early disrepair phase, before irreparable structural damage has occurred. Fortunately, previous experimental studies have shown that depletion of GAGs from tendon fascicles does not decrease tensile stiffness 40 147 151 152. We, therefore, speculate that this treatment, which has been used in different medical applications for over 60 years, could be safe for tendons as well 153–155…”

“…On the other hand, drug treatment that directly targets the elevated GAG content might also be a very powerful tool. A potential treatment that has been mentioned recently for tendinopathies is human recombinant hyaluronidase, as it degrades HA, CS and DS from the ECM to preinjury levels 147 148. The removal of these excess GAGs can liberate the bound fluid and significantly reduce the fluid content, resulting in a lower IRP, thus enabling vascular re-expansion 101 140 149.…”

Animal model for tendinopathy

“…The TGF-β1 injection model was established by injecting 100 ​ng of TGF-β1 into the mice Achilles tendon on days 0 and 2 [ 60 , 61 ]. Rezvani et al.…”

“…Rezvani et al. showed that increased cellularity and rounded nucleus on day 6 [ 60 ]. Then, cartilage metaplasia and hyaluronan accumulation occurred in the tendon tissue on days 9 and 25.…”

Discovery to delivery in tendon research

“…Reviews cover the state of our understanding of normal and diabetic tendon healing and the role of the extracellular matrix in tendon development and homeostatis . A series of original research papers delves into tendon pathogenesis and healing, focusing on a broad range of topics: the effect of age and fatigue on tendon biomechanics, transcriptomics analysis of tendon healing, and treatment strategies that include hyaluronidase, pulsed electromagnetic fields, and parathyroid hormone . A collection of stem cell papers describes methods to generate and optimize stem cells and uses them to enhance tendon healing .…”