Osteoblastic Responses to LPS, Glucose-oxidised LDL and Minocycline: Therapeutic Targets for Periodontal and Cardiometabolic Diseases

Abstract

Objectives: To study redox responses of cultured osteoblasts, mediated by bacterial lipopolysaccharide (LPS), glucose (G), glucose-oxidised low density lipoprotein (GLDL) and minocycline (M) using radiolabelled steroid markers of redox status and wound healing. The clinical relevance of this concept in periodontitis patients with cardiometabolic risk markers is addressed. Methods: A well differentiated osteoblastic cell-line was cultured in Eagle's MEM in confluent monolayer, in 24 well multiwell plates. Radiolabelled testosterone was used as the steroid substrate. Experiments were set up with controls in the absence of agents, optimal concentrations (previously determined) of G, GLDL, LPS, M, GLDL+LPS and the latter combined with M (n = 8). At the end of a 24h incubation period, the reaction was terminated and the medium analysed for yields of the steroid metabolite 5 -dihydrotestosterone (DHT), the redox marker relevant to wound healing, the weaker androgen 4-androstenedione (4-A) and the diols. Analysis entailed thin layer chromatography and radioisotope scanning. Results: The yields of DHT showed 1.4-fold and 2.3-fold decreases in response to GLDL and LPS respectively and a 1.3-fold reduction in response to the combination, when compared with controls in the absence of agents. Minocycline stimulated the yield of DHT by 1.4-fold, and when combined with GLDL+LPS, the decreased yield was overcome and raised to 2-fold above the combination in response to the addition of minocycline (n = 8; p < 0.001), when compared with controls. The trends in the yields of 4-A and diols were inversely related to each other with increases and decreases over controls respectively, in keeping with enzymic pathways. Conclusions: Decreased yields of the oxidative stress marker DHT in response to LPS, G and GLDL were overcome in the presence of minocycline, which demonstrates its potential role as an adjunctive therapeutic agent in an environment of oxidative stress. These applications could be extrapolated to periodontal disease and co-existing cardiometabolic risk markers, in the context of its antiinflammatory and antioxidant actions relevant to healing. In this paper, recent patents relevant to adjunctive therapeutic management of periodontal disease co-existing with cardiometabolic risk markers are addressed. There have been significant advances in therapeutic interventions for overcoming oxidative stress-inducing mechanisms that are common to these disease entities.

Anti-inflammatory Actions of Adjunctive Tetracyclines and Other Agents in Periodontitis and Associated Comorbidities

“…AGE products could initiate the production of TNF-α, IL-6, IL-18 and reactive oxygen species (ROS) which would contribute to chemical modification of lipoproteins and atherogenesis in diabetics [81]. Some of the oxidant effects of AGE are overcome by the antioxidant glutathione [105], suggestive of a role for tetracyclines as therapeutic adjuncts in this context. It is relevant that in cultured osteoblasts, decreased yields of anti-oxidant markers in response to bacterial lipopolysaccharide, glucose and glucose-oxidized low-density lipoprotein were overcome in response to minocycline [106]; thus reinforcing its potential actions as an antioxidant in an environment of oxidative stress.…”

Periodontal disease: the influence of metabolic syndrome

“…In fact, in addition to its antimicrobial effect, it shows antioxidant, anti-inflammatory, proanabolic, immunomodulatory, angiogenetic, and antiapoptotic effects [33,34]. Decreased yields of oxidative stress were also obtained in the presence of minocycline, which demonstrates its potential role as an adjunctive therapeutic agent in an environment of oxidative stress, such as in periodontal disease and coexisting cardiometabolic pathologies [35]. Then, the beneficial systemic effect of the antioxidant tempol on apical periodontitis in both control and pathological rats with doxorubicin-elicited cardiomyopathy has also been evidenced [36].…”

Influence of Apical Periodontitis on Stress Oxidative Parameters in Diabetic Rats

“…This understanding will also aid in the development of new therapies with an aim to modulate oxidative stress (14,15). These therapies might help reduce the symptoms related to periapical lesions (16), periodontal disease (17), and diabetes (18,19). Therefore, the aim of this study was to evaluate if AP alters the oxidative stress parameters such as albumin, bilirubin, uric acid, the total antioxidant capacity (TAC), and malondialdehyde (MDA) in normoglycemic and diabetic rats.…”