Obesity remains the most important risk factor for the incidence and progression of osteoarthritis (OA). The leading cause of OA was believed to be overloading the joints due to excess weight which ...in turn leads to the destruction of articular cartilage. However, recent studies have proved otherwise, various other factors like adipose deposition, insulin resistance, and especially the improper coordination of innate and adaptive immune responses may lead to the initiation and progression of obesity-associated OA. It is becoming increasingly evident that multiple inflammatory cells are recruited into the synovial joint that serves an important role in pathological changes in the synovial joint. Polarization of macrophages and macrophage-produced mediators are extensively studied and linked to the inflammatory and destructive responses in the OA synovium and cartilage. However, the role of other major innate immune cells such as neutrophils, eosinophils, and dendritic cells in the pathogenesis of OA has not been fully evaluated. Although cells of the adaptive immune system contribute to the pathogenesis of obesity-induced OA is still under exploration, a quantity of literature indicates OA synovium has an enriched population of T cells and B cells compared with healthy control. The interplay between a variety of immune cells and other cells that reside in the articular joints may constitute a vicious cycle, leading to pathological changes of the articular joint in obese individuals. This review addresses obesity and the role of all the immune cells that are involved in OA and summarised animal studies and human trials and knowledge gaps between the studies have been highlighted. The review also touches base on the interventions currently in clinical trials, different stages of the testing, and their shortcomings are also discussed to understand the future direction which could help in understanding the multifactorial aspects of OA where inflammation has a significant function.
As direct effector cells for osteogenesis, osteoblastic cells are commonly used for evaluating the in vitro osteogenic capacity of bone biomaterials, and the traditional biological principle for ...developing bone biomaterials is to directly stimulate osteogenic differentiation. With this principle, most efforts are currently spent on optimizing the bio-mechanical and physicochemical properties to induce osteogenic differentiation of mesenchymal stem cells. This strategy has achieved certain success in the development of bone biomaterials; however, inconsistencies between in vitro and in vivo studies are not uncommon, implying the mechanisms that govern the material's capacity to mediate osteogenesis is not well-understood. Osteoimmunology has revealed the vital role of immune cells in regulating bone dynamics. Neglecting the importance of the immune response is a major shortcoming of the traditional strategy, and may explain inconsistencies between in vitro and in vivo conditions. Here, we proposed osteoimmunomodulation (OIM) in recognition of the importance of the immune response during biomaterial-mediated osteogenesis. Accordingly, we proposed the paradigm shift of bone biomaterials to an osteoimmunomodulatory material and discussed the evaluation strategy for the osteoimmunomodulation property of bone biomaterials. It is the ambition of authors that this review will change traditional methods for bone biomaterials assessment and assist in developing new bone biomaterials with the osteoimmunomodulatory property for orthopedic and dental applications.
Mesenchymal stem cells (MSCs) are multipotent cells that can differentiate into various cell types and have been widely used in tissue engineering application. In tissue engineering, a scaffold, MSCs ...and growth factors are used as essential components and their interactions have been regarded to be important for regeneration of tissues. A critical problem for MSCs in tissue engineering is their low survival ability and functionality. Most MSCs are going to be apoptotic after transplantation. Therefore, increasing MSC survival ability and functionalities is the key for potential applications of MSCs. Several approaches have been studied to increase MSC tissue forming capacity including application of growth factors, overexpression of stem cell regulatory genes, and improvement of biomaterials for scaffolds. The effects of these approaches on MSCs have been associated with activation of the phosphoinositide 3-kinase (PI3K)/Akt signaling pathway. The pathway plays central regulatory roles in MSC survival, proliferation, migration, angiogenesis, cytokine production, and differentiation. In this review, we summarize and discuss the literatures related to the roles of the PI3K/Akt pathway in the functionalities of MSCs and the involvement of the pathway in biomaterials-increased MSC functionalities. Biomaterials have been modified in their properties and surface structure and loaded with growth factors to increase MSC functionalities. Several studies demonstrated that the biomaterials-increased MSC functionalities are mediated by the activation of the PI3K/Akt pathway.
The osteoimmune environment plays indispensable roles in bone regeneration because the early immune environment that exists during the regenerative process promotes the recruitment and ...differentiation of osteoblastic lineage cells. The response of immune cells growing on nanotopographic surfaces and the microenvironment they generate should be considered when evaluating nanotopography-mediated osteogenesis, which are topics that are generally neglected in the field. In this study, we investigated the modulatory effects of nanoporous anodic alumina with different sized pores on macrophage responses and their subsequent effects on the osteogenic differentiation of bone marrow stromal cells (BMSCs). The nanopore structure and the pore size were found to be important adhesive cues for macrophages, which affected their spreading and cell shape, subsequently regulated the expression and activation of autophagy pathway components (LC3A/B, Beclin-1, Atg3, Atg7, and P62) and modulated the inflammatory response, osteoclastic activities, and release of osteogenic factors. Subsequently, the osteogenic pathways (Wnt and BMP) of BMSCs were found to be regulated by different nanopore-induced inflammatory environments, which affected the osteogenic differentiation outcomes. This study is the first to emphasize the effects of immune cells on nanotopography-mediated osteogenesis, which could lead to a new strategy for the development of advanced nanobiomaterials for tissue engineering, nanomedicine and immunotherapeutic applications.
Abstract The periosteum plays an indispensable role in both bone formation and bone defect healing. In this study we constructed an artificial in vitro periosteum by incorporating osteogenic ...differentiated bone marrow stromal cells (BMSCs) and cobalt chloride (CoCl2 )-treated BMSCs. The engineered periostea were implanted both subcutaneously and into skull bone defects in SCID mice to investigate ectopic and orthotopic osteogenesis and vascularization. After two weeks in subcutaneous and four weeks in bone defect areas, the implanted constructs were assessed for ectopic and orthotopic osteogenesis and vascularization by micro-CT, histomorphometrical and immunohistochemical methods. The results showed that CoCl2 pre-treated BMSCs induced higher degree of vascularization and enhanced osteogenesis within the implants in both ectopic and orthotopic areas. This study provided a novel approach using BMSCs sourced from the same patient for both osteogenic and pro-angiogenic purposes in constructing tissue engineered periosteum to enhance vascularized osteogenesis.
Abstract
Background
It is well-known that both macrophages and osteocytes are critical regulators of osteogenesis and osteoclastogenesis, yet there is limited understanding of the ...macrophage-osteocyte interaction, and how their crosstalk could affect bone homeostasis and mineralization. This research therefore aims to investigate the effects of macrophage polarization on osteocyte maturation and mineralization process.
Methods
A macrophage-derived conditioned medium based osteocyte culture was set up to investigate the impact of macrophages on osteocyte maturation and terminal mineralization. Surgically induced osteoarthritis (OA) rat model was used to further investigate the macrophage-osteocyte interaction in inflammatory bone remodeling, as well as the involvement of the Notch signaling pathway in the mineralization process.
Results
Our results identified that osteocytes were confined in an immature stage after the M1 macrophage stimulation, showing a more rounded morphology, higher expression of early osteocyte marker E11, and significantly lower expression of mature osteocyte marker DMP1. Immature osteocytes were also found in inflammatory bone remodeling areas, showing altered morphology and mineralized structures similar to those observed under the stimulation of M1 macrophages in vitro, suggesting that M1 macrophages negatively affect osteocyte maturation, leading to abnormal mineralization. The Notch signaling pathway was found to be down regulated in M1 macrophage-stimulated osteocytes as well as osteocytes in inflammatory bone. Overexpression of the Notch signaling pathway in osteocytes showed a significant circumvention on the negative effects from M1 macrophage.
Conclusion
Taken together, our findings provide valuable insights into the mechanisms involved in abnormal bone mineralization under inflammatory conditions.
We report two Australian patients with possible cobalt toxicity related to metal-on-metal total hip replacements. Both patients were treated for osteoarthritis with a DePuy ASR (articular surface ...replacement) XL Acetabular Hip System prosthesis, which contains cobalt and chromium, and which has recently been recalled from the market.
The contribution of metabolic factors on the severity of osteoarthritis (OA) is not fully appreciated. This study aimed to define the effects of hyper cholesterolemia on the progression of OA. A ...polipoprotein E‐deficient (ApoE−/−) mice and rats with diet‐induced hypercholesterolemia (DIHC) rats were used to explore the effects of hyper cholesterolemia on the progression of OA. Both models exhibited OA‐like changes, characterized primarily by a loss of proteoglycans, collagen and aggrecan degradation, osteophyte formation, changes to subchondral bone architecture, and cartilage degradation. Surgical destabilization of the knees resulted in a dramatic increase of degradative OA symptoms in animals fed a high‐cholesterol diet compared with controls. Clinically relevant doses of free cholesterol resulted in mitochondrial dysfunction, overproduction of reactive oxygen species (ROS), and increased expression of degenerative and hypertrophic markers in chondrocytes and breakdown of the cartilage matrix. We showed that the severity of diet‐induced OA changes could be attenuated by treatment with both atorvastatin and a mitochondrial targeting antioxidant. The protective effects of the mitochondrial targeting antioxidant were associated with suppression of oxidative damage to chondrocytes and restoration of extracellular matrix homeostasis of the articular chondrocytes. In summary, our data show that hypercholesterolemia precipitates OA progression by mitochondrial dysfunction in chondrocytes, in part by increasing ROS production and apoptosis. By addressing the mitochondrial dysfunction using antioxidants, we were able attenuate the OA progression in our animal models. This approach may form the basis for novel treatment options for this OA risk group in humans.—Farnaghi, S., Prasadam, I., Cai, G., Friis, T., Du, Z., Crawford, R., Mao, X., Xiao, Y. Protective effects of mitochondria‐targeted antioxidants and statins on cholesterolinduced osteoarthritis. FASEB J. 31, 356–367 (2017) www.fasebj.org
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