PubMed · 9567099
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C Misch. 1995. Progressive bone loading.. https://pubmed.ncbi.nlm.nih.gov/9567099/
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Estrogen deficiency in the postmenopausal (PM) female is the major cause of osteoporosis and may contribute to increased periodontal disease, including alveolar bone loss, seen in these women. In the current study, an animal model of PM osteoporosis, the OVX adult female rat, was studied to determine: (i) the relationship between periodontal breakdown and skeletal bone loss, and (ii) the effect of CMT-8 on gingival collagenase and bone loss. OVX rats were daily gavaged with CMT-8 (1, 2, or 5 mg/rat) for 28 or 90 days; non-OVX rats and those gavaged with vehicle alone served as controls. Elevated collagenase activity, assessed using [3H-methyl] collagen as substrate in the presence or absence of APMA, was seen in the gingiva of the OVX rats, and CMT-8 therapy suppressed this effect. Western blot revealed a similar pattern for MMP-8 and MMP-13 concentrations. The changes in the gingival collagenase activity paralleled changes in periodontal bone loss, which, in turn, reflected trabecular bone density changes. Preliminary studies on PM humans administered sub-antimicrobial tetracycline as a matrix metalloproteinase inhibitor are under way.
Both Type I and Type II diabetes mellitus (DM) have been associated with unusually aggressive periodontitis. Accordingly, rat models of both types of DM were used to study (i) mechanisms mediating this systemic/local interaction and (ii) new pharmacologic approaches involving a series of chemically modified tetracyclines (CMTs) that have lost their antimicrobial but retained their host-modulating (e.g., MMP-inhibitory) properties. In vitro experiments on tissues from Type I DM rats demonstrated that several of these CMTs were better matrix metalloproteinase (MMP) inhibitors than was antibacterial doxycycline (doxy), except for CMT-5, which, unlike the other MMP inhibitors, was found not to react with zinc. Data from in vivo studies on the same rat model generally supported the relative efficacy of these compounds: the CMTs and doxy were found to inhibit MMP activity, enzyme expression, and alveolar bone loss. To examine other long-term complications such as nephropathy and retinopathy, a Type II (ZDF) model of DM was studied. Treatment of these DM rats with CMT-8 produced a 37% (p < 0.05), 93% (p < 0.001), and 50% (p < 0.01) reduction in the incidence of cataract development, proteinuria, and tooth loss, respectively; whereas the doxy-treated ZDF rats showed little or no effect on these parameters. CMT treatment decreased mortality of the Type II ZDF diabetic animals, clearly indicating that CMTs, but not commercially available antibiotic tetracyclines (TCs), may have therapeutic applications for the long-term management of diabetes.
C-telopeptides and related pyridinoline cross-links of bone Type I collagen are sensitive markers of bone resorption in osteolytic diseases such as osteoporosis and osteoarthritis. We have studied the release of C-telopeptide pyridinoline crosslinks of Type I collagen as measures of bone destruction in periodontal disease. Studies in preclinical animal models and humans have demonstrated the relationship between radiographic bone loss and crevicular fluid C-telopeptide levels. We have recently found that C-telopeptide levels correlate strongly with microbial pathogens associated with periodontitis and around endosseous dental implants. Host-modulation of bone-related collagen breakdown has been shown by studies in humans demonstrating that MMP inhibition blocks tissue destruction and release of C-telopeptides in patients with active periodontal disease.