Mechanism of action and morphologic changes in the alveolar bone in response to selective alveolar decortication–facilitated tooth movement

Macrophage cell fusion and multinucleation are fundamental processes in the formation of multinucleated giant cells (MGCs) in chronic inflammatory disease and osteoclasts in the regulation of bone mass. However, this basic cell phenomenon is poorly understood despite its pathophysiological relevance. Granulomas containing multinucleated giant cells are seen in a wide variety of complex inflammatory disorders, as well as in infectious diseases. Dysregulation of osteoclastic bone resorption underlies the pathogenesis of osteoporosis and malignant osteolytic bone disease. Recent reports have shown that the formation of multinucleated giant cells and osteoclast fusion display a common molecular signature, suggesting shared genetic determinants. In this Review, we describe the background of cell–cell fusion and the similar origin of macrophages and osteoclasts. We specifically focus on the common pathways involved in osteoclast and MGC fusion. We also highlight potential approaches that could help to unravel the core mechanisms underlying bone and granulomatous disorders in humans.

Common signalling pathways in macrophage and osteoclast multinucleation.

Bone mass can be viewed as the net product of two counteracting metabolic processes, bone formation and bone resorption, which allow the skeleton to carry out its principal functions: mechanical support of the body, calcium dynamic deposition and haemopoiesis. Besides radiological methods, several blood and urinary molecules have been identified as markers of bone metabolic activity for estimating the rates and direction of the biological activities governing bone turnover. The advantages for the use of bone metabolism markers are that they are potentially less dangerous than radiological determinations, are more sensitive to changes in bone metabolism than radiological methods and are easily collected and analysed. The disadvantages are that they have high biological variability. Physical exercise is a known source of bone turnover and is recommended for preventing osteoporosis and bone metabolism problems. There are numerous experiments on bone metabolism markers after acute exercise, but not after long-term training and during or after a whole competition season. Moreover, few studies on bone metabolism markers have evaluated their performance in elite and top-level athletes, who have a higher bone turnover than sedentary individuals. Despite discrepant results among studies, most have shown that short exercise is insufficient for modifying serum concentrations of bone metabolism markers. Marker variations are more evident after several hours or days after exercise, bone formation markers are more sensitive than bone resorption markers, and stimulation of osteoblast and/or osteoclast functions is exercise dependent but the response is not immediate. The response depends on the type of exercise; the markers seem to be less sensitive to resistance exercise and the intensity of exercise is not discriminate. Comparisons between trained subjects and untrained controls have demonstrated the influence of exercise on bone turnover. During training, carboxy-terminal collagen cross-links (CTx), a bone resorption marker, was shown to be less sensitive than amino-terminal cross-linking telopeptide of type I collagen (NTx) and urinary pyridinolines, which were sensitive to anaerobic exercise. Whereas, the bone formation markers, bone alkaline phosphatase (BAP) and osteocalcin (OC) changed after 1 month and 2 months of an exercise programme, respectively. After 2 months, while BAP normalized, it was found to be sensitive to aerobic exercise and OC was found to be sensitive to anaerobic exercise. After prolonged training and competition, bone formation markers are found to change in sedentary subjects enrolled in a physical activity programme. Professional athletes show changes in bone formation markers depending on programme intensity, whereas bone resorption appears to stabilize. Crucial for long-term training, are the characteristics of exercise (e.g. weight-bearing, impact).

Bone metabolism markers in sports medicine.

Osteoporosis mainly affects postmenopausal women and older men. Gastrointestinal hormones released after meal ingestion, such as glucose-dependent insulinotropic peptide (GIP) and glucagon-like peptide (GLP)-2, have been shown to regulate bone turnover. However, whether GLP-1, another important gastrointestinal hormone, and its analogues also have antiosteoporotic effects, especially in aged postmenopausal situation, has not been confirmed. In the present study, we evaluated the effects of the GLP-1 receptor agonist exendin-4 on ovariectomy (OVX)-induced osteoporosis in old rats. Twelve-month-old female Sprague-Dawley rats were subjected to OVX, and exendin-4 was administrated 4 weeks after the surgery and lasted for 16 weeks. Bone characters and related serum and gene biomarkers were analyzed. Sixteen weeks of treatment with exendin-4 slowed down body weight gain by decreasing fat mass and prevented the loss of bone mass in old OVX rats. Exendin-4 also enhanced bone strength and prevented the deterioration of trabecular microarchitecture. Moreover, exendin-4 decreased the urinary deoxypyridinoline (DPD)/creatinine ratio and serum C-terminal cross-linked telopeptides of type I collagen (CTX-I) and increased serum alkaline phosphatase (ALP), osteocalcin (OC), and N-terminal propeptide of type 1 procollagen (P1NP) levels, key biochemical markers of bone turnover. Interestingly, gene expression results further showed that exendin-4 not only inhibited bone resorption by increasing the osteoprotegerin (OPG)/receptor activator of NF-κB ligand (RANKL) ratio, but also promoted bone formation by increasing the expression of OC, Col1, Runx2, and ALP, which exhibited dual regulatory effects on bone turnover as compared with previous antiosteoporotic agents. In conclusion, these findings demonstrated for the first time the antiosteoporotic effects of exendin-4 in old OVX rats and that it might be a potential candidate for treatment of aged postmenopausal osteoporosis.

Exendin-4, a Glucagon-Like Peptide-1 Receptor Agonist, Prevents Osteopenia by Promoting Bone Formation and Suppressing Bone Resorption in Aged Ovariectomized Rats

Flavonoids of Herba Epimedii regulate osteogenesis of human mesenchymal stem cells through BMP and Wnt/β-catenin signaling pathway.

Bone remodelling is a process by which bone grows and turns over. This process involves a series of highly regulated steps that depend on the interaction of two cell lineages, the osteoclasts and the osteoblasts. Information on metabolic activity of bone tissue are achieved with the determination, in blood and in urine, of biochemical products derived from the activity of this cells. The ability to determine bone turnover with biochemical markers has been enhanced considerably in recent years with the development of new assays for more sensitive and specific markers. These new markers can now replace the outdated and non-specific markers of bone remodeling such as serum total alkaline phosphatase (ALP) and urinary hydroxyproline (Hyp) determination. Biochemical markers of bone turnover can be classified according to the process that underlie in markers of bone formation, products of the osteoblast activity [bone ALP, osteocalcin (OC), procollagene I C- and N-terminal propeptides] and markers of bone resorption, products of the osteocalst activity [pyridinuim crosslinks, collagen I C- and N-terminal telopeptides (CTX-I and NTX-I), tartrate resistent acid phosphatase (TRACP) isoform 5b]. The interpretation of laboratory results should always include the consideration of potential sources of variability. Variation in the results of biochemical markers of bone metabolism can compromise their ability to characterize disorders of bone metabolism. Variation can be categorized into pre-analytical, analytical and biological sources. However, the determination of biochemical markers of bone turnover offers many advantages in clinical practice, since they are non-invasive, can be repeated often, and major changes occur in a short time.

Markers of bone turnover: biochemical and clinical perspectives.

Bone tissue is subject to remodeling throughout the lifetime of an individual. Through a continuous remodeling cycle, actuated via the so-called 'bone remodeling units', old bone is resorbed by osteoclasts with the formation of cavities that are subsequently filled by osteoblasts. Bone loss observed in old age and in women after menopause is due to an imbalance between bone resorption and formation. Biochemical markers provide a dynamic view of the remodeling process, which covers rate of turnover and pathogenesis, and should improve fracture risk prediction. Furthermore, they can be used to monitor the short-term effects of therapy, and indicate if an excessive slowing of the remodeling process is occurring. When searching for markers of bone remodeling, biochemists have focused mainly on skeletal molecules that can be dosed in plasma and/or urine, as indicators of osteoblast function (i.e. bone alkaline phosphatase, osteocalcin, procollagene I C- and N-terminal propeptides) or osteoclast function (i.e. pyridinium crosslinks, collagen I C- and N-terminal telopeptides). The clinical significance of any marker for bone remodeling depends on two fundamental characteristics: specificity and variability. If the objective is to monitor therapeutic efficacy, it seems most rational to use a resorption marker for drugs that act principally on osteoclast, such as estrogens or bisphosphonates, while for drugs that act principally on osteoblast, such as PTH-peptides a marker for bone formation would be more appropriate.

F Pagani

Papers

Markers of bone turnover: biochemical and clinical perspectives.

Role of biochemical markers of bone remodeling in clinical practice