Periodontitis (PD) is a chronic osteolytic disease that shares pathogenic inflammatory features with other conditions associated with nonresolving inflammation. A hallmark of PD is inflammation‐mediated alveolar bone loss. Myeloid cells, in particular polymorphonuclear neutrophils (PMN) and macrophages (Mac), are essential players in PD by control of gingival biofilm pathogenicity, activation of adaptive immunity, as well as nonresolving inflammation and collateral tissue damage. Despite mounting evidence of significant innate immune implications to PD progression and healing after therapy, myeloid cell markers and targets for immune modulation have not been validated for clinical use. The remarkable plasticity of monocytes/Mac in response to local activation factors enables these cells to play central roles in inflammation and restoration of tissue homeostasis and provides opportunities for biomarker and therapeutic target discovery for management of chronic inflammatory conditions, including osteolytic diseases such as PD and arthritis. Along a wide spectrum of activation states ranging from proinflammatory to pro‐resolving, Macs respond to environmental changes in a site‐specific manner in virtually all tissues. This review summarizes the existing evidence on Mac immunomodulation therapies for osteolytic diseases in the broader context of conditions associated with nonresolving inflammation, and discusses osteoimmune implications of Macs in PD.

Progression of inflammatory osteolytic diseases, including rheumatoid arthritis and periodontitis, is characterized by increased production of proinflammatory mediators and matrix-degrading enzymes by macrophages and increased osteoclastic activity. Phenotypic changes in macrophages are central to the healing process in virtually all tissues. Using a murine model of periodontitis, we assessed the timing of macrophage phenotypic changes and the impact of proresolving activation during inflammatory osteolysis and healing. Proinflammatory macrophage activation and TNF-α overproduction within 3 wk after induction of periodontitis was associated with progressing bone loss. Proresolving activation within 1 wk of stimulus removal and markers of resolving macrophages (IL-10, TGF-β, and CD206) correlated strongly with bone levels. In vivo macrophage depletion with clodronate liposomes prevented bone resorption but impaired regeneration. Induction of resolving macrophages with rosiglitazone, a PPAR-γ agonist, led to reduced bone resorption during inflammatory stimulation and increased bone formation during healing. In vitro assessment of primary bone marrow-derived macrophages activated with either IFN-γ and LPS (proinflammatory activation) or IL-4 (proresolving activation) showed that IL-4-activated cells have enhanced resolving functions (production of anti-inflammatory cytokines; migration and phagocytosis of aged neutrophils) and exert direct anabolic actions on bone cells. Cystatin C secreted by resolving but not inflammatory macrophages explained, in part, the macrophage actions on osteoblasts and osteoclasts. This study supports the concept that therapeutic induction of proresolving functions in macrophages can recouple bone resorption and formation in inflammatory osteolytic diseases.

Treatment with MSE in EP actually caused healing of bone, and these effects are probably related to decreases in local oxidative damage and osteoclast activity. Given MSE's positive effects on osteodifferentiation as well, these findings suggest that MSE could be a useful therapeutic agent for the management of periodontitis.

Osteoclast differentiation and function are highly dependent on the assembly and turnover of actin filaments, but little is known about the roles of actin binding proteins in these processes. Adseverin (Ads), a member of the gelsolin superfamily of actin capping and severing proteins, regulates actin filament turnover and can regulate the turnover of cortical actin filaments of chromaffin cells during exocytosis. Using a conditional Ads knockout mouse model, we confirmed our previous finding in cultured cells that Ads plays a role in osteoclastogenesis (OCG) and actin cytoskeletal organization in osteoclasts. Here we show that Ads is required for osteoclast formation and that when alveolar bone resorption is experimentally induced in mice, genetic deletion of Ads prevents osteoclast-mediated bone loss. Further, when Ads-null osteoclasts are cultured, they exhibit defective OCG, disorganized podosome-based actin filament superstructures, and decreased bone resorption. Reintroduction of Ads into Ads-null osteoclast precursor cells restored these osteoclast defects. Collectively, these data demonstrate a unique and osteoclastspecific role for Ads in OCG and osteoclast

Cystatin C is a low-molecular-weight biomarker that meets the conditions necessary to be a marker of the glomerular filtration rate. This endogenous cysteine proteinase inhibitor belonging to the type 2 cystatin superfamily plays a key role in health and disease. Human cystatin C is encoded by the CST3 gene, ubiquitously expressed at moderate levels throughout the body, given it is produced in all nucleated cells in a constant amount. It is present in all human body fluids, and may be determined in the serum, plasma, capillary blood and urine. In this review, we present and discuss most of the available data from the literature for the use of cystatin C in clinical practice. In addition to a kidney function marker, studies suggest cystatin C could be used as a marker for cardiovascular risk assessment, in predicting and detecting preeclampsia, in patients with malignant neoformations, etc. Local cystatin C deficiency has also been demonstrated in atherosclerosis, aneurismal lesions, among others, suggesting a protective role of cystatin C. Far beyond its humble beginning, it promises uses from prognosis to treatments for everything from prostate cancer to periodontal disease. Cystatin C has begun its journey into a multitude of disciplines; we can only begin to imagine the many more purposes yet to find going forward.