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    Macrophage: A Potential Target on Cartilage Regeneration. Fernandes Tiago Lazzaretti,Gomoll Andreas H,Lattermann Christian,Hernandez Arnaldo Jose,Bueno Daniela Franco,Amano Mariane Tami Frontiers in immunology Cartilage lesions and osteoarthritis (OA) presents an ever-increasing clinical and socioeconomic burden. Synovial inflammation and articular inflammatory environment are the key factor for chondrocytes apoptosis and hypertrophy, ectopic bone formation and OA progression. To effectively treat OA, it is critical to develop a drug that skews inflammation toward a pro-chondrogenic microenvironment. In this narrative and critical review, we aim to see the potential use of immune cells modulation or cell therapy as therapeutic alternatives to OA patients. Macrophages are immune cells that are present in synovial lining, with different roles depending on their subtypes. These cells can polarize to pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes, being the latter associated with wound-healing by the production of ARG-1 and pro-chondrogenic cytokines, such as IL-10, IL-1RA, and TGF-b. Emerging evidence reveals that macrophage shift can be determined by several stimuli, apart from the conventional IL-4, IL-13, and IL-10. Evidences show the potential of physical exercise to induce type 2 response, favoring M2 polarization. Moreover, macrophages in contact with oxLDL have effect on the production of anabolic mediators as TGF-b. In the same direction, type II collagen, that plays a critical role in development and maturation process of chondrocytes, can also induce M2 macrophages, increasing TGF-b. The mTOR pathway activation in macrophages was shown to be able to polarize macrophages , though further studies are required. The possibility to use mesenchymal stem cells (MSCs) in cartilage restoration have a more concrete literature, besides, MSCs also have the capability to induce M2 macrophages. In the other direction, M1 polarized macrophages inhibit the proliferation and viability of MSCs and impair their ability to immunosuppress the environment, preventing cartilage repair. Therefore, even though MSCs therapeutic researches advances, other sources of M2 polarization are attractive issues, and further studies will contribute to the possibility to manipulate this polarization and to use it as a therapeutic approach in OA patients. 10.3389/fimmu.2020.00111
    Controlling the Phenotype of Macrophages Promotes Maturation of Tissue-Engineered Cartilage. Fujihara Yuko,Abe Takahiro,Hoshi Kazuto Tissue engineering. Part A Tissue reactions after transplantation can affect the maturation and prognosis of the transplanted engineered tissue in regenerative medicine. Since macrophages are broadly subdivided into two major phenotypes, inflammatory (M1) and anti-inflammatory/wound healing (M2), in this study, we examined the properties of macrophages in transplantation of tissue-engineered cartilage, to clarify their effects on cartilage maturation. Human chondrocytes were embedded in a poly-L-lactic acid scaffold, which was transplanted subcutaneously on the back in athymic mice. When the constructs were analyzed by real-time polymerase chain reaction, interleukin 1 expression was detectable at 4 days, and it reached a peak at 7 days. Interleukin 6 expression was increased at 7 to 11 days, suggesting that M1 macrophages were abundant around this time. On the other hand, expression of markers for M2 macrophages occurred rather later, with and expression peaking at around 11 to 14 days, possibly indicating that polarization of macrophages in tissue-engineered cartilage could shift from M1 to M2 around 11 days after transplantation. When cultured by using the conditioned medium of M2 macrophages, chondrocytes showed significantly increased expression of type 2 collagen, suggesting that M2 macrophages could enhance the maturation of tissue-engineered cartilage. Also, by partially depleting macrophages with clodronate liposomes in the initial period, during which M1 macrophages were dominant, more cartilage matrix accumulated in transplanted constructs at 2 weeks. It was suggested that polarization of macrophages shifted from M1 to M2 in the transplantation of tissue-engineered cartilage, and controlling the polarization could be advantageous for the maturation of transplanted engineered tissues. Impact statement In transplantation of engineered tissues, it is imperative for immune reactions to proceed in a proper and timely manner. In this study, we transplanted tissue-engineered cartilage consisting of a biodegradable polymer scaffold and chondrocytes, and examined the properties of macrophages. It was shown that the polarization of macrophages shifted from inflammatory (M1) to anti-inflammatory/wound healing (M2) around 11 days after transplantation. Partial suppression of macrophages at the early stage of transplantation, which were mainly M1 macrophages, promoted more accumulation of cartilage matrix. This study indicates a possible approach to facilitate cartilage maturation by intervening in the polarity of macrophages. 10.1089/ten.TEA.2019.0190
    Anti-inflammatory/tissue repair macrophages enhance the cartilage-forming capacity of human bone marrow-derived mesenchymal stromal cells. Sesia Sergio B,Duhr Ralph,Medeiros da Cunha Carolina,Todorov Atanas,Schaeren Stefan,Padovan Elisabetta,Spagnoli Giulio,Martin Ivan,Barbero Andrea Journal of cellular physiology Macrophages are key players in healing processes. However, little is known on their capacity to modulate the differentiation potential of mesenchymal stem/stromal cells (MSC). Here we investigated whether macrophages (Mf) with, respectively, pro-inflammatory and tissue-remodeling traits differentially modulate chondrogenesis of bone marrow derived-MSC (BM-MSC). We demonstrated that coculture in collagen scaffolds of BM-MSC with Mf derived from monocytes polarized with M-CSF (M-Mf), but not with GM-CSF (GM-Mf) resulted in significantly higher glycosaminoglycan (GAG) content than what would be expected from an equal number of BM-MSC alone (defined as chondro-induction). Moreover, type II collagen was expressed at significantly higher levels in BM-MSC/M-Mf as compared to BM-MSC/GM-Mf constructs, while type X collagen expression was unaffected. In order to understand the possible cellular mechanism accounting for chondro-induction, developing monoculture and coculture tissues were digested and the properties of the isolated BM-MSC analysed. We observed that as compared to monocultures, in coculture with M-Mf, BM-MSC decreased less markedly in number and exhibited higher clonogenic and chondrogenic capacity. Despite their chondro-inductive effect in vitro, M-Mf did not modulate the cartilage tissue maturation in subcutaneous pockets of nude mice, as evidenced by similar accumulation of type X collagen and calcified tissue. Our results demonstrate that coculture of BM-MSC with M-Mf results in synergistic cartilage tissue formation in vitro. Such effect seems to result from the survival of BM-MSC with high chondrogenic capacity. Studies in an orthotopic in vivo model are necessary to assess the clinical relevance of our findings in the context of cartilage repair. 10.1002/jcp.24861
    Cartilage repair in degenerative osteoarthritis mediated by squid type II collagen via immunomodulating activation of M2 macrophages, inhibiting apoptosis and hypertrophy of chondrocytes. Dai Meilu,Sui Baiyan,Xue Yang,Liu Xin,Sun Jiao Biomaterials Cartilage lesions in degenerative osteoarthritis (OA) are involved with pathological microenvironmental alterations induced by inflammatory macrophages, and apoptotic and/or hypertrophic chondrocytes. However, current non-operative therapies for cartilage repair in OA can rarely achieve long-term and satisfactory outcomes. This study aims to evaluate a newly developed squid type II collagen (SCII) for repairing OA-induced cartilage lesions. Our in vitro data show that SCII induces M2 polarization of macrophages, and activates macrophages to express pro-chondrogenic genes (TGF-β and IGF), which greatly improves the microenvironment around chondrocytes to produce type II collagen and glycosaminoglycan. In addition, glycine in SCII activates glycine receptors on inflammatory chondrocytes to decrease intracellular calcium concentration, leading to effective inhibition of chondrocyte apoptosis and hypertrophy. The in vitro effects of SCII are further confirmed in vivo. In a rat model of OA, SCII increases the ratio of M2 macrophages, elevates the levels of pro-chondrogenic cytokines (TGF-β1 and TGF-β3) in synovial fluid, and inhibits chondrocyte apoptosis and MMP13 production. Our findings show that SCII immunomodulates M2 activation of macrophages to skew the local OA microenvironment towards a pro-chondrogenic atmosphere, and promotes cartilage repair under inflammatory condition. It shows great potential for SCII to be a novel biomaterial for cartilage repair in OA. 10.1016/j.biomaterials.2018.07.011
    Faecal microbiota transplantation from metabolically compromised human donors accelerates osteoarthritis in mice. Huang ZeYu,Chen Jing,Li BoLei,Zeng Benhua,Chou Ching-Heng,Zheng Xin,Xie JingWei,Li Hao,Hao Yu,Chen Guo,Pei FuXing,Shen Bin,Kraus Virginia B,Wei Hong,Zhou Xuedong,Cheng Lei Annals of the rheumatic diseases OBJECTIVES:Emerging evidence suggests that the microbiome plays an important role in the pathogenesis of osteoarthritis (OA). We aimed to test the two-hit model of OA pathogenesis and potentiation in which one 'hit' is provided by an adverse gut microbiome that activates innate immunity; the other 'hit' is underlying joint damage. METHODS:Medical history, faecal and blood samples were collected from human healthy controls (OA-METS-, n=4), knee OA without metabolic syndrome (OA+METS-, n=7) and knee OA with metabolic syndrome (OA+METS+, n=9). Each group of human faecal samples, whose microbial composition was identified by 16S rRNA sequencing, was pooled and transplanted into germ-free mice 2 weeks prior to meniscal/ligamentous injury (MLI) (n≥6 per group). Eight weeks after MLI, mice were evaluated for histological OA severity and synovitis, systemic inflammation and gut permeability. RESULTS:Histological OA severity following MLI was minimal in germ-free mice. Compared with the other groups, transplantation with the OA+METS+ microbiome was associated with higher mean systemic concentrations of inflammatory biomarkers (interleukin-1β, interleukin-6 and macrophage inflammatory protein-1α), higher gut permeability and worse OA severity. A greater abundance of and and lesser abundance of in transplanted mice were consistently correlated with OA severity and systemic biomarkers concentrations. CONCLUSION:The study clearly establishes a direct gut microbiome-OA connection that sets the stage for a new means of exploring OA pathogenesis and potentially new OA therapeutics. Alterations of , and suggest a role of these particular microbes in exacerbating OA. 10.1136/annrheumdis-2019-216471
    Synovial macrophage M1 polarisation exacerbates experimental osteoarthritis partially through R-spondin-2. Zhang Haiyan,Lin Chuangxin,Zeng Chun,Wang Zhenyu,Wang Hua,Lu Jiansen,Liu Xin,Shao Yan,Zhao Chang,Pan Jianying,Xu Song,Zhang Yue,Xie Denghui,Cai Daozhang,Bai Xiaochun Annals of the rheumatic diseases OBJECTIVES:To investigate the roles and regulatory mechanisms of synovial macrophages and their polarisation in the development of osteoarthritis (OA). METHODS:Synovial tissues from normal patients and patients with OA were collected. M1 or M2-polarised macrophages in synovial tissues of patients with OA and OA mice were analysed by immunofluorescence and immunohistochemical staining. Mice with tuberous sclerosis complex 1 (TSC1) or Rheb deletion specifically in the myeloid lineage were generated and subjected to intra-articular injection of collagenase (collagenase-induced osteoarthritis, CIOA) and destabilisation of the medial meniscus (DMM) surgery to induce OA. Cartilage damage and osteophyte size were measured by Osteoarthritis Research Society International score and micro-CT, respectively. mRNA sequencing was performed in M1 and control macrophages. Mice and ATDC5 cells were treated with R-spondin-2 (Rspo2) or anti-Rspo2 to investigate the role of Rspo2 in OA. RESULTS:M1 but not M2-polarised macrophages accumulated in human and mouse OA synovial tissue. TSC1 deletion in the myeloid lineage constitutively activated mechanistic target of rapamycin complex 1 (mTORC1), increased M1 polarisation in synovial macrophages and exacerbated experimental OA in both CIOA and DMM models, while Rheb deletion inhibited mTORC1, enhanced M2 polarisation and alleviated CIOA in mice. The results show that promoting the macrophage M1 polarisation leads to exacerbation of experimental OA partially through secretion of Rspo2 and activation of β-catenin signalling in chondrocytes. CONCLUSIONS:Synovial macrophage M1 polarisation exacerbates experimental CIOA partially through Rspo2. M1 macrophages and Rspo2 are potential therapeutic targets for OA treatment. 10.1136/annrheumdis-2018-213450