Systemic Administration of Bone-Targeting Anabolic Drug Mes-1022 to Accelerate Early Bone Healing
Meghan Morrella,b, Jack Chapmana,b,c, Elena Nehmea,d, Meet Shaha,b, Taylor DeVeta,b,c, Catherine Juliena,b, Frank Raucha,b,e, Bettina M. Williea,b,c
aResearch Centre, Shriners Hospital for Children-Canada, Montreal, bFaculty of Dental Medicine and Oral Health Sciences, ÎÛÎÛ²ÝÝ®ÊÓƵ University, Montreal, cDepartment of Bioengineering and Biomedical Engineering, ÎÛÎÛ²ÝÝ®ÊÓƵ University, Montreal, dFaculty of Arts and Science, Concordia University, Montreal, eDepartment of Pediatrics, ÎÛÎÛ²ÝÝ®ÊÓƵ University, Montreal,
Introduction: Non-union rates for all fractures are estimated to be approximately 10%(1). There is a need to improve effectiveness of current pharmacological anabolic therapies(2). MES-1022 is
a novel bone-targeted prostaglandin E2 receptor 4 agonist prodrug(3). The aim of this study was to examine the capacity of systemically administered MES-1022 to accelerate early bone healing
in a noncritical sized femoral segmental defect in rats. Methods: We created a 1mm mid-diaphyseal osteotomy in the left femur of 37 male Sprague Dawley rats randomized into 5 treatment groups: MES-1022 at 10mg/kg, MES-1022 at 5mg/kg, MES-1022 at 1mg/kg, MES-1022 at 0.2mg/kg and PBS + 25nM EDTA at 0.5ml (vehicle). Osteotomies were stabilized with a unilateral external fixator (Rat ExFix, RISystem), and rats were euthanized at 7 days post-osteotomy. Assessment of healing of the osteotomized femur included analysis of blood serum bone markers (P1NP, ALP, and TRAcP-5b), µCT, and histomorphometry at day 7 of callus tissue composition using Movat Pentachrome stained paraffin embedded sections. Mechanical testing and µCT analysis of non-operated femurs and assessment of organ weight is ongoing. An independent t-test assessed the effect of treatment for µCT and histomorphometry data. An ANOVA assessed treatment, time and interactions for serum bone markers, followed by post-hoc Tukey tests, with significance at p≤0.05.
Results: ANOVA indicated time of blood collection had a significant effect on P1NP, ALP, and TRAcP-5b (p<0.002). As expected there was no difference in P1NP, ALP, or TRAcP-5b between treatment groups at baseline. At day 7, we saw greater ALP levels in 5mg and 10mg compared to vehicle (p<0.028). P1NP was higher in the 1mg, 5mg, and 10mg compared to vehicle (p<0.032). Also at day 7, we did not observe differences between treatment groups for µCT outcomes. Importantly, at day 7 there was no difference in callus tissue composition between treatment groups.
Conclusion: We did not observe differences in callus tissue composition, including cartilage during the early phase of healing. These findings suggest that MES-1022 did not accelerate the early chondral stage of fracture healing. However, the significance seen in the Tukey tests in ALP and P1NP in the 10mg, 5mg, and 1mg groups suggests that bone formation was increased. Examination of healing at 6-weeks post-osteotomy is ongoing to determine the effectiveness of MES-1022 in the later stages of bone healing.
Conflicts of Interest: None declared.
References: (1) Rupp et al., (2017). Inter. Orthop., 42(2), 247–258. (2) Tägil et al., (2010). Bone, 46(3), 852–859. (3) Sheikh et al., (2019). JBMR plus, 3(12), e10237