Effects of zoledronic acid and geranylgeraniol on the cellular behaviour and gene expression of primary human alveolar osteoblasts

This review describes normal bone anatomy and physiology as an introduction to the subsequent articles in this section that discuss clinical applications of iliac crest bone biopsy. The normal anatomy and functions of the skeleton are reviewed first, followed by a general description of the processes of bone modeling and remodeling. The bone remodeling process regulates the gain and loss of bone mineral density in the adult skeleton and directly influences bone strength. Thorough understanding of the bone remodeling process is critical to appreciation of the value of and interpretation of the results of iliac crest bone histomorphometry. Osteoclast recruitment, activation, and bone resorption is discussed in some detail, followed by a review of osteoblast recruitment and the process of new bone formation. Next, the collagenous and noncollagenous protein components and function of bone extracellular matrix are summarized, followed by a description of the process of mineralization of newly formed bone matrix. The actions of biomechanical forces on bone are sensed by the osteocyte syncytium within bone via the canalicular network and intercellular gap junctions. Finally, concepts regarding bone remodeling, osteoclast and osteoblast function, extracellular matrix, matrix mineralization, and osteocyte function are synthesized in a summary of the currently understood functional determinants of bone strength. This information lays the groundwork for understanding the utility and clinical applications of iliac crest bone biopsy.

Background Chronic inflammation is a characteristic feature of diabetic cutaneous wounds. We sought to delineate novel mechanisms involved in the impairment of resolution of inflammation in diabetic cutaneous wounds. At the wound-site, efficient dead cell clearance (efferocytosis) is a pre-requisite for the timely resolution of inflammation and successful healing. Methodology/Principal Findings Macrophages isolated from wounds of diabetic mice showed significant impairment in efferocytosis. Impaired efferocytosis was associated with significantly higher burden of apoptotic cells in wound tissue as well as higher expression of pro-inflammatory and lower expression of anti-inflammatory cytokines. Observations related to apoptotic cell load at the wound site in mice were validated in the wound tissue of diabetic and non-diabetic patients. Forced Fas ligand driven elevation of apoptotic cell burden at the wound site augmented pro-inflammatory and attenuated anti-inflammatory cytokine response. Furthermore, successful efferocytosis switched wound macrophages from pro-inflammatory to an anti-inflammatory mode. Conclusions/Significance Taken together, this study presents first evidence demonstrating that diabetic wounds suffer from dysfunctional macrophage efferocytosis resulting in increased apoptotic cell burden at the wound site. This burden, in turn, prolongs the inflammatory phase and complicates wound healing.

Chemokines are seen as the stimuli that largely control leukocyte migration. To assess whether the severely impaired process of cutaneous repair observed in genetically diabetic db/db mice is associated with a dysregulated infiltration of immune cells, we determined the expressional kinetics for the murine growth-regulated oncogene/melanoma growth stimulatory activity homolog macrophage inflammatory protein-2, and the macrophage chemoattractant protein-1, respectively. Wound repair in db/db mice was characterized by a sustained inflammatory response and a prolonged expression of macrophage inflammatory protein-2 and macrophage chemoattractant protein-1. Immuno-histochemistry revealed that keratinocytes at the wound margins expressed macrophage chemoattractant protein-1, whereas macrophage inflammatory protein-2 immunopositive signals were observed only in keratinocytes of hair follicles located adjacent to the wound site. Inactivation studies using neutralizing antibodies against macrophage chemoattractant protein-1 or macrophage inflammatory protein-2 indicated that sustained expression of these chemokines participated in a prolonged presence of neutrophils and macrophages at the wound site during diabetic repair. Furthermore, our data provide evidence that late infiltration (day 13 after injury) of neutrophils and macrophages into wounds in db/db mice was associated with a simultaneous downregulation of mRNA for receptors specific for macrophage inflammatory protein-2 and macrophage chemoattractant protein-1 in these animals.