Journal of Inflammation Research (Feb 2023)
Efficacy of a Novel Pleiotropic MMP-Inhibitor, CMC2.24, in a Long-Term Diabetes Rat Model with Severe Hyperglycemia-Induced Oral Bone Loss
Abstract
Heta Dinesh Bhatt,1 Lorne M Golub,1 Hsi-Ming Lee,1 Jihwan Kim,2 Thomas Zimmerman,3 Jie Deng,4 Houlin Hong,5 Francis Johnson,6 Ying Gu7 1Department of Oral Biology and Pathology, School of Dental Medicine, Stony Brook University, Stony Brook, NY, USA; 2Department of Pediatric Dentistry, University of Buffalo School of Dental Medicine, Buffalo, NY, USA; 3Division of Laboratory Animal Resources (DLAR) at Stony Brook, Stony Brook University, Stony Brook, NY, USA; 4Department of Orthodontics, Peking University School and Hospital of Stomatology & National Clinical Research Center for Oral Diseases & National Engineering Laboratory for Digital and Material Technology of Stomatology & Beijing Key Laboratory of Digital Stomatology, Beijing, People’s Republic of China; 5Department of Community Health & Social Sciences, Graduate School of Public Health & Health Policy, City University of New York, New York City, NY, USA; 6Department of Chemistry and Pharmacological Sciences, School of Medicine, Stony Brook University, Stony Brook, NY, USA; 7Department of General Dentistry, School of Dental Medicine, Stony Brook University, Stony Brook, NY, USACorrespondence: Heta Dinesh Bhatt, Department of Oral Biology and Pathology, School of Dental Medicine, Stony Brook University, Stony Brook, NY, 11794, USA, Tel +1631820-5311, Email [email protected]: CMC2.24, a novel 4-(phenylaminocarbonyl)-chemically-modified-curcumin, is a pleiotropic MMP-Inhibitor of various inflammatory/collagenolytic diseases including periodontitis. This compound has demonstrated efficacy in host modulation therapy along with improved resolution of inflammation in various study models. The objective of current study is to determine the efficacy of CMC2.24 in reducing the severity of diabetes, and its long-term role as an MMP-inhibitor, in a rat model.Methods: Twenty-one adult male Sprague-Dawley rats were randomly distributed into three groups: Normal (N), Diabetic (D) and Diabetic+CMC2.24 (D+2.24). All three groups were orally administered vehicle: carboxymethylcellulose alone (N, D), or CMC2.24 (D+2.24; 30mg/kg/day). Blood was collected at 2-months and 4-months’ time-point. At completion, gingival tissue and peritoneal washes were collected/analyzed, and jaws examined for alveolar bone loss by micro-CT. Additionally, sodium hypochlorite(NaClO)-activation of human-recombinant (rh) MMP-9 and its inhibition by treatment with 10μM CMC2.24, Doxycycline, and Curcumin were evaluated.Results: CMC2.24 significantly reduced the levels of lower-molecular-weight active-MMP-9 in plasma. Similar trend of reduced active-MMP-9 was also observed in cell-free peritoneal and pooled gingival extracts. Thus, treatment substantially decreased conversion of pro- to actively destructive proteinase. Normalization of the pro-inflammatory cytokine (IL-1ß, resolvin-RvD1), and diabetes-induced osteoporosis was observed in presence of CMCM2.24. CMC2.24 also exhibited significant anti-oxidant activity by inhibiting the activation of MMP-9 to a lower-molecular-weight (82kDa) pathologically active form. All these systemic and local effects were observed in the absence of reduction in severity of hyperglycemia.Conclusion: CMC2.24 reduced activation of pathologic active-MMP-9, normalized diabetic osteoporosis, and promoted resolution of inflammation but had no effect on the hyperglycemia in diabetic rats. This study also highlights the role of MMP-9 as an early/sensitive biomarker in the absence of change in any other biochemical parameter. CMC2.24 also inhibited significant activation of pro-MMP-9 by NaOCl (oxidant) adding to known mechanisms by which this compound treats collagenolytic/inflammatory diseases including periodontitis.Keywords: matrix metalloproteinases, diabetes mellitus, resolvin, anti-oxidant activity, host modulation therapy
