EFFECTIVENESS OF COMBINED FORMULATIONS OF HYADD^®4 AND ALENDRONATE OR RAPAMYCIN IN AN IN VIVO MODEL OF OSTEOARTHRITIS ON OVARIECTOMIZED RATS

HYADD®4 is a hexadecylamide derivative of Hyaluronan (HA) forming hydrogels with excellent lubricating and viscoelastic properties, widely used as viscosupplement in the treatment of knee OA. In this study, the effects of the intra-articular (i.a.) injection of FID-337, a ready-to-use formulation of HYADD®4 + Alendronate (ALN), and FID-338, a combined treatment based on HYADD®4 + Rapamycin (RAP), were evaluated on an OA model obtained by destabilization of the medial meniscus (DMM) performed in ovariectomized (OVX) female rats. Eight-week-old female Sprague Dawley rats were ovariectomized and after four weeks underwent DMM surgery on the right knee. Four weeks after, the animals were randomly divided into 4 groups of 9 rats each according to knee joint i.a. treatment, administered every 2 weeks (a total of 3 injections): FID-337, FID-338, HYADD®4 and saline; sham-operated rats (SHAM) were used as control. Mechanical allodynia was assessed weekly by the Von Frey test. Four weeks after the third i.a. injection rats were sacrificed. Microtomography (micro-CT) analysis was performed to assess bone volume, trabecular thickness and separation, and bone mineral density. Hematoxylin–eosin and safranin O/fast green staining were used to evaluate cartilage degradation, which was quantified through the OARSI score, and proteoglycan (PG) content. Withdrawal thresholds, which were low and unchanged over time in rats treated with saline, increased after the first injection of each treatment, reached levels of the SHAM group by the 10 th week in the FID-338 group while continued to increase until the end of the study in the FID-337 group. The bone architecture was altered in NaCl-treated rats, and partially restored only after treatment with FID-337, FID-338 or HYADD Ò 4. In the same groups, the synovial membrane was better preserved compared to the saline group. The OARSI (Fig.1) and PG loss scores were significantly lower in HYADD®4-treated joints and even further reduced significantly with FID-337 or FID-338 treatment. I.a. administration of HYADD®4 with ALN or RAP significantly impacts the OA progression, reducing pain and preventing cartilage damage in the OVX+DMM rat model, which describes a specific OA endotype. The local administration could maximize the local benefit while reducing the well known systemic side effects and this may lead to the development of a novel therapy with repurposed drugs combined with the HA-based viscosupplement. For any figures or tables, please contact the authors directly.