Resolving Macrophages Counter Osteolysis by Anabolic Actions on Bone Cells

Abstract

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.

Characterization of macrophages infiltrating peri‐implantitis lesions

“…The current literature on macrophage polarization does not have a clear consensus on markers to identify M1 polarization and M2 polarization, and emerging data suggest an increased complexity on the differentiation of macrophages dependent on environmental cues. Few studies proposed staining protocols for activated macrophages with iNOS (He et al, ; Tang, Zhao, Lei, Chen, & Zhang, ), CCR7 (Wang, Li, Feng, Cheng, & Li, ) for detecting M1 phenotypes, while others used CD206 (Viniegra et al, ) (Lee et al, ; Nawaz et al, ; C. Zhang et al, ) or CD163 (Ham et al, ; Wang et al, ) for M2 phenotypes. The presence of subtypes of macrophage polarization like M2a, M2b, M2c, and M2d also remains to be defined in periodontal diseases.…”

“…Macrophage polarization has been a complex topic with conflicting data in periodontal disease research (Viniegra et al, ; Yang et al, ; Yu et al, ; S. Zhang et al, ). Much of the discrepancy may be associated with technical challenges, such as the selection of molecular markers capable of identifying changes in macrophage polarization.…”

Macrophage immunomodulation in chronic osteolytic diseases—the case of periodontitis

“…The relative contribution of innate and adaptive immune cells to onset of bone loss can be dissected through selective cell depletion or alterations of critical functions such as recruitment, reactive oxygen/nitrogen species, and cytokine production . Importantly, ligature experimental PD can be reversed when ligatures are removed after onset of bone loss, allowing for investigation of resolution of periodontal inflammation and bone regeneration, and the testing of therapeutics to enhance the latter . This is specifically important for understanding the relationship between “constructive” and “destructive” inflammation governed by Mac in view of their central roles in regulation of tissue homeostasis.…”

“…PPAR‐γ controls iMac activation in part by interfering with proinflammatory signaling pathways AP‐1, NF‐kB, or STAT‐1 suggesting that TZDs may be particularly efficient for PD management . Indeed, rosiglitazone had a positive impact on alveolar bone preservation and regeneration in experimental PD . The anabolic actions of rosiglitazone were attributed in part to inhibition of osteoclast formation despite favoring adipogenesis over osteoblast differentiation in bone marrow mesenchymal stem cells .…”

“…The reduction in bone quality and mass, which is a well‐documented side effect of long‐term TZDs treatment, is partially explained by induction of adipogenesis in bone marrow stromal cells and decreased osteoblast and aromatase activities . We recently found short‐term rosiglitazone treatment in mice with experimental PD to enhance bone regeneration through direct anabolic action on bone cells by inhibition of osteoclast activity and stimulation of bone mineral deposition by osteoblasts . The positive impact of rMac activation on bone was in part explained by increased production of anti‐proteases and bone anabolic proteins.…”