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Ding M, Ding Q, Liu Z, Wang L, Pei K, Hu J, Liao Y, Zhang JV. TNFRSF11B-modified umbilical cord mesenchymal stem cells as a novel strategy for bone-related diseases by suppressing osteoclast activity. J Orthop Surg Res 2025; 20:478. [PMID: 40380204 PMCID: PMC12085028 DOI: 10.1186/s13018-025-05850-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2025] [Accepted: 04/23/2025] [Indexed: 05/19/2025] Open
Abstract
BACKGROUND AND OBJECTIVE Mesenchymal stem cells (MSCs), possessing multilineage potential, are capable of differentiating into osteoblasts and thus serve as suitable seed cells for bone regeneration. Tumor necrosis factor receptor superfamily member 11B (TNFRSF11B) gene encodes osteoprotegerin (OPG), which has a critical role in repressing osteoclast differentiation and has been reported to influence the adipogenic differentiation of bone marrow mesenchymal stem cells (BMMSCs). Nevertheless, the impact of TNFRSF11B on the osteogenic differentiation of umbilical cord mesenchymal stem cells (UCMSCs) remains unclear. This study aimed to investigate the role of TNFRSF11B in the osteogenesis of UCMSCs and bone remodeling. METHODS Differentially expressed genes (DEGs) were identified from the GEO database using R software. TNFRSF11B was transduced into UCMSCs by a lentiviral vector. Cell differentiation capacity was assessed by ALP staining, TRAP staining, and qRT-PCR assay. Proteomic analysis was performed to investigate the key proteins in TNFRSF11B-OE-UCMSCs that inhibit osteoclast differentiation. RESULTS We found that the TNFRSF11B gene was upregulated during osteogenic differentiation and downregulated during adipogenic differentiation of UCMSCs. UCMSCs overexpressing the TNFRSF11B gene were successfully generated via lentivirus transfection. However, neither the overexpression of TNFRSF11B nor treatment with exogenous OPG protein was sufficient to enhance the osteogenic potential of UCMSCs in vitro. Conditioned medium from TNFRSF11B-overexpressing UCMSCs significantly suppressed RANKL-induced osteoclast differentiation, while no significant effect was observed on osteoblast differentiation compared to the control group. Proteome analysis revealed that in the TNFRSF11B-OE-CM group, the expression of C1R, MDH1, and ACLY was significantly downregulated, while the expression of FETUB and METRNL was upregulated in the TNFRSF11B-OE-CM group, which was associated with the inhibition of osteoclast differentiation. CONCLUSION This study demonstrates that although TNFRSF11B overexpression does not promote osteogenesis in UCMSCs, it may participate in regulating bone remodeling by inhibiting osteoclast differentiation.
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Affiliation(s)
- Mina Ding
- Shenzhen Key Laboratory of Metabolic Health, Center for Energy Metabolism and Reproduction, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China
- Shenzhen Beike Biotechnology Co., Ltd, Shenzhen, 518054, China
| | - Qian Ding
- Shenzhen Beike Biotechnology Co., Ltd, Shenzhen, 518054, China
| | - Zhijie Liu
- Shenzhen Beike Biotechnology Co., Ltd, Shenzhen, 518054, China
| | - Liang Wang
- Shenzhen Beike Biotechnology Co., Ltd, Shenzhen, 518054, China
| | - Ke Pei
- Shenzhen Beike Biotechnology Co., Ltd, Shenzhen, 518054, China
| | - Junyuan Hu
- Shenzhen Beike Biotechnology Co., Ltd, Shenzhen, 518054, China
- Shenzhen Beike Biotechnology Research Institute, Shenzhen, 518054, China
| | - Yan Liao
- Shenzhen Beike Biotechnology Co., Ltd, Shenzhen, 518054, China.
- Shenzhen Beike Biotechnology Research Institute, Shenzhen, 518054, China.
| | - Jian V Zhang
- Shenzhen Key Laboratory of Metabolic Health, Center for Energy Metabolism and Reproduction, Shenzhen Institutes of Advanced Technology, Chinese Academy of Sciences, Shenzhen, 518055, China.
- Faculty of Pharmaceutical Sciences, Shenzhen University of Advanced Technology, Shenzhen, 518055, China.
- Sino-European Center of Biomedicine and Health, Shenzhen, 518055, China.
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Li F, Cui S. Knockdown of C3aR alleviates age-related bone loss via activation of YAP1/β-catenin signaling. J Biol Chem 2025; 301:108500. [PMID: 40216253 DOI: 10.1016/j.jbc.2025.108500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Revised: 03/13/2025] [Accepted: 03/30/2025] [Indexed: 05/12/2025] Open
Abstract
The complement system plays an important role in bone growth during physiological development and skeletal homeostasis. However, the specific impact of the complement C3a receptor (C3aR) on age-related bone loss remains unclear. In this study, we found that C3aR expression increased with age and was the same as that of the senescent molecules p53, p21, and p16 in control mice. Knockdown of C3aR reduced the expression of senescence markers and significantly ameliorated bone senescence. Notably, C3aR knockdown in mice effectively reversed age-induced bone loss, which was characterized by an increase in the number of osteoblasts and a decrease in the number of osteoclasts. In an in vitro model of D-gal-induced senescence, increased expression of C3aR correlated with increased expression of senescence markers such as p53, p21, and p16. Treatment with a C3aR antagonist (JR14a) successfully attenuated the expression of these markers of cellular senescence and reduced the proportion of late apoptotic cells. Mechanistically, JR14a treatment mitigated D-gal-mediated inhibition of osteoblastic differentiation in preosteoblasts through activation of the YAP1/β-catenin signaling pathway. In the D-gal-induced aging mouse model, treatment with JR14a ameliorates bone microarchitecture and bone loss. In summary, these studies revealed a role for C3aR in regulating bone homeostasis, suggesting that targeting C3aR may be a promising therapeutic strategy for the treatment of age-related osteoporosis.
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Affiliation(s)
- Fangyu Li
- Department of Rheumatology and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Endocrinology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shun Cui
- Department of Rheumatology and Immunology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Ren F, Zheng S, Luo H, Yu X, Li X, Song S, Bu W, Sun H. Fibroblast derived C3 promotes the progression of experimental periodontitis through macrophage M1 polarization and osteoclast differentiation. Int J Oral Sci 2025; 17:30. [PMID: 40240339 PMCID: PMC12003657 DOI: 10.1038/s41368-025-00361-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2024] [Revised: 02/20/2025] [Accepted: 03/05/2025] [Indexed: 04/18/2025] Open
Abstract
Complement C3 plays a critical role in periodontitis. However, its source, role and underlying mechanisms remain unclear. In our study, by analyzing single-cell sequencing data from mouse model of periodontitis, we identified that C3 is primarily derived from periodontal fibroblasts. Subsequently, we demonstrated that C3a has a detrimental effect in ligature-induced periodontitis. C3ar-/- mice exhibited significantly less destruction of periodontal support tissues compared to wild-type mice, characterized by mild gingival tissue damage and reduced alveolar bone loss. This reduction was associated with decreased production of pro-inflammatory mediators and reduced osteoclast infiltration in the periodontal tissues. Mechanistic studies suggested that C3a could promote macrophage polarization and osteoclast differentiation. Finally, by analyzing single-cell sequencing data from the periodontal tissues of patients with periodontitis, we found that the results observed in mice were consistent with human data. Therefore, our findings clearly demonstrate the destructive role of fibroblast-derived C3 in ligature-induced periodontitis, driven by macrophage M1 polarization and osteoclast differentiation. These data strongly support the feasibility of C3a-targeted interventions for the treatment of human periodontitis.
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Affiliation(s)
- Feilong Ren
- Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, School and Hospital of Stomatology, Jilin University, Changchun, China
| | - Shize Zheng
- Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, School and Hospital of Stomatology, Jilin University, Changchun, China
| | - Huanyu Luo
- Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, School and Hospital of Stomatology, Jilin University, Changchun, China
| | - Xiaoyi Yu
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, School and Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory Oral Biomedical Engineering, Jilin University, Changchun, China
| | - Xianjing Li
- Hospital of Stomatology, Jilin University, Changchun, China
| | - Shaoyi Song
- Hospital of Stomatology, Jilin University, Changchun, China
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, School and Hospital of Stomatology, Jilin University, Changchun, China
| | - Wenhuan Bu
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, School and Hospital of Stomatology, Jilin University, Changchun, China.
- Jilin Provincial Key Laboratory Oral Biomedical Engineering, Jilin University, Changchun, China.
| | - Hongchen Sun
- Hospital of Stomatology, Jilin University, Changchun, China.
- Jilin Provincial Key Laboratory of Tooth Development and Bone Remodeling, School and Hospital of Stomatology, Jilin University, Changchun, China.
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Regnier M, Leclerc ALS, Tenenbaum J, Desjonqueres M, Chavassieux P, Fremeaux-Bacchi V, Farlay D, Bacchetta J. Bone impairment in atypical hemolytic and uremic syndrome treated by long-term eculizumab. Pediatr Nephrol 2025; 40:961-965. [PMID: 39422762 PMCID: PMC11885323 DOI: 10.1007/s00467-024-06564-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2024] [Revised: 09/09/2024] [Accepted: 10/03/2024] [Indexed: 10/19/2024]
Abstract
Atypical hemolytic uremic syndrome (aHUS) is a thrombotic microangiopathy, related to complement dysregulation, including Factor H deficiency (FH) treated by lifelong eculizumab therapy. Its long-term tolerance is not yet fully described. We report two patients with genetic FH deficiency receiving long-term eculizumab and displaying a peculiar bone phenotype. First case is a 13-year-old girl, presenting with bone pains, arthritis, and deformities, for which X-rays and MRI described multifocal osteochondritis. Bone biopsy revealed an active remodeling bone (many areas of bone formation and resorption) and C3c accumulation on immunohistochemical staining. The second patient is an 11-year-old girl, displaying mechanical bone pains, for which bone scintigraphy found hypofixation of wrists and ankles. These findings could be consistent with a side effect of eculizumab, as C3c accumulation may result from the downstream C5-blockade. Alternatively, bone alterations could be due to the absence of FH, as described in murine models. Further investigations are required to characterize bone disease in aHUS.
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Affiliation(s)
- Maitena Regnier
- Centre de Référence Des Maladies Rénales Rares, Centre de Référence Des Maladies Rares du Calcium Et du Phosphore, Filières Maladies Rares ORKID Et OSCAR, Hospices Civils de Lyon & Université Claude-Bernard Lyon 1, Lyon, France
- Service de Néphrologie, Rhumatologie Et Dermatologie Pédiatriques, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Boulevard Pinel, 69677, Bron Cedex, France
| | - Anne-Laure Sellier Leclerc
- Centre de Référence Des Maladies Rénales Rares, Centre de Référence Des Maladies Rares du Calcium Et du Phosphore, Filières Maladies Rares ORKID Et OSCAR, Hospices Civils de Lyon & Université Claude-Bernard Lyon 1, Lyon, France
- Service de Néphrologie, Rhumatologie Et Dermatologie Pédiatriques, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Boulevard Pinel, 69677, Bron Cedex, France
| | - Julie Tenenbaum
- Service de Néphrologie Pédiatrique, CHU de Montpellier, Montpellier, France
| | - Marine Desjonqueres
- Service de Néphrologie, Rhumatologie Et Dermatologie Pédiatriques, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Boulevard Pinel, 69677, Bron Cedex, France
| | - Pascale Chavassieux
- INSERM, UMR 1033, Univ Lyon, Université Claude Bernard Lyon 1, 69008, Lyon, France
| | - Véronique Fremeaux-Bacchi
- Assistance Publique-Hôpitaux de Paris, Department of Immunology Biology, European Hospital Georges Pompidou, Paris, France
- INSERM, UMRS1138, Centre de Recherche Des Cordeliers, Team "Inflammation, Complement and Cancer", Paris, France
| | - Delphine Farlay
- INSERM, UMR 1033, Univ Lyon, Université Claude Bernard Lyon 1, 69008, Lyon, France
| | - Justine Bacchetta
- Centre de Référence Des Maladies Rénales Rares, Centre de Référence Des Maladies Rares du Calcium Et du Phosphore, Filières Maladies Rares ORKID Et OSCAR, Hospices Civils de Lyon & Université Claude-Bernard Lyon 1, Lyon, France.
- Service de Néphrologie, Rhumatologie Et Dermatologie Pédiatriques, Hôpital Femme Mère Enfant, Hospices Civils de Lyon, Boulevard Pinel, 69677, Bron Cedex, France.
- INSERM, UMR 1033, Univ Lyon, Université Claude Bernard Lyon 1, 69008, Lyon, France.
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Zhu W, Yang Z, Zhou S, Zhang J, Xu Z, Xiong W, Liu P. Modic changes: From potential molecular mechanisms to future research directions (Review). Mol Med Rep 2025; 31:90. [PMID: 39918002 PMCID: PMC11836598 DOI: 10.3892/mmr.2025.13455] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2024] [Accepted: 01/14/2025] [Indexed: 02/13/2025] Open
Abstract
Low back pain (LBP) is a leading cause of disability worldwide. Although not all patients with Modic changes (MCs) experience LBP, MC is often closely associated with LBP and disc degeneration. In clinical practice, the focus is usually on symptoms related to MC, which are hypothesized to be associated with LBP; however, the link between MC and nerve compression remains unclear. In cases of intervertebral disc herniation, nerve compression is often the definitive cause of symptoms. Recent advances have shed light on the pathophysiology of MC, partially elucidating its underlying mechanisms. The pathogenesis of MC involves complex bone marrow‑disc interactions, resulting in bone marrow inflammation and edema. Over time, hematopoietic cells are gradually replaced by adipocytes, ultimately resulting in localized bone marrow sclerosis. This process creates a barrier between the intervertebral disc and the bone marrow, thereby enhancing the stability of the vertebral body. The latest understanding of the pathophysiology of MC suggests that chronic inflammation plays a significant role in its development and hypothesizes that the complement system may contribute to its pathological progression. However, this hypothesis requires further research to be confirmed. The present review we proposed a pathological model based on current research, encompassing the transition from Modic type 1 changes (MC1) to Modic type 2 changes (MC2). It discussed key cellular functions and their alterations in the pathogenesis of MC and outlined potential future research directions to further elucidate its mechanisms. Additionally, it reviewed the current clinical staging and pathogenesis of MC, recommended the development of an updated staging system and explored the prospects of integrating emerging artificial intelligence technologies.
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Affiliation(s)
- Weijian Zhu
- Department of Orthopedics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430077, P.R. China
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Zhou Yang
- Department of Orthopedics, Hongxin Harmony Hospital, Li Chuan, Hubei 445400 P.R. China
| | - Sirui Zhou
- Department of Respiration, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430077, P.R. China
| | - Jinming Zhang
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Zhihao Xu
- Department of Hepatobiliary Surgery, Huaqiao Hospital, Jinan University, Guangzhou, Guangdong 510630, P.R. China
| | - Wei Xiong
- Department of Orthopedics, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, P.R. China
| | - Ping Liu
- Department of Orthopedics, Liyuan Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430077, P.R. China
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Jiang F, Zhang Y, Peng F, Liu H, Ding K, Cao P, Liu X, Li L, Liu Z, Fu R. Complement C3a promotes the formation of osteoclasts by inhibiting Sirt1 to activate the PI3K/PDK1/SGK3 pathway in patients with multiple myeloma. J Transl Med 2025; 23:338. [PMID: 40091033 PMCID: PMC11912697 DOI: 10.1186/s12967-025-06319-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2025] [Accepted: 02/24/2025] [Indexed: 03/19/2025] Open
Abstract
BACKGROUND Myeloma bone disease (MBD) is the most common complication of multiple myeloma (MM). Our previous study showed that the complement C3a activates osteoclasts to participate in the pathogenesis of MBD; however, its mechanism of action is diverse and complex. Studies have shown that the Sirtuin (Sirt) family of proteins (i.e., Sirt1-7) are expressed in human bone and cartilage, and participate in bone metabolic balance. METHODS AND RESULTS We measured the levels of complement C3a, Sirt1, osteoclast-related genes, and bone disease-related biological indicators using enzyme-linked immunosorbent assay (ELISA), quantitative real-time PCR and western blotting. Sirt1 expression in osteoclasts was observed to be lower in patients with MM compared to healthy donors and negatively correlated with complement C3a levels, osteoclast-related gene expression, and osteolysis-related markers. Co-immunoprecipitation (Co-IP) and immunostaining were used to verify the interaction between C3a and Sirt1 in RAW264.7 cells. Osteoclasts were then induced from bone marrow mononuclear cells (BMMCs) in patients with MM or cultured RAW264.7 cells, using C3a and/or Sirt1 activator (SRT1720)/inhibitors (EX527) in vitro. Sirt1 inhibits osteoclast formation and complement C3a reverses this inhibitory function of Sirt1 to activate osteoclasts. RAW264.7 cells with induced overexpression or knockdown Sirt1 were transfected with plasmid or shRNA, and RNA-seq analysis was performed. Increased Sirt1 expression resulted in the inhibition of the PI3K/PDK1/SGK3 pathway, which could be reactivated by complement C3a. Sirt1 knockdown activated the PI3K/PDK1/SGK3 pathway, which was further enhanced by complement C3a. A mouse model of MBD was successfully constructed. We injected this model with complement C3a or SRT1720, which further verified that complement C3a can significantly increase the degree of MBD bone damage, whereas SRT1720 can reduce the bone damage aggravated by C3a and treat MBD. CONCLUSION We demonstrated that complement C3a interacts with Sirt1 in osteoclasts to participate in the pathogenesis of MBD. Complement C3a promotes osteoclast formation by inhibiting Sirt1 to activate the PI3K/PDK1/SGK3 pathway in patients with MM, which is reduced by treatment with a Sirt1 activator. The application of a Sirt1 activator can reduce the formation of osteoclasts and reduce the severity of bone diseases in vivo and may be useful for the treatment of MBD. This study identified novel potential therapeutic targets and strategies for patients with MBD.
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Affiliation(s)
- Fengjuan Jiang
- Department of Hematology, Tianjin Medical University General Hospital, 154 Anshan Street, Heping District, Tianjin, 300052, China
- Tianjin Key Laboratory of Bone Marrow Failure and Malignant Hemopoietic Clone Control, Tianjin, 300052, China
- Tianjin Institute of Hematology, Tianjin, 300052, China
| | - Yunhe Zhang
- Department of Hematology, Tianjin Medical University General Hospital, 154 Anshan Street, Heping District, Tianjin, 300052, China
- Tianjin Key Laboratory of Bone Marrow Failure and Malignant Hemopoietic Clone Control, Tianjin, 300052, China
- Tianjin Institute of Hematology, Tianjin, 300052, China
| | - Fengping Peng
- Department of Hematology, Tianjin Medical University General Hospital, 154 Anshan Street, Heping District, Tianjin, 300052, China
- Tianjin Key Laboratory of Bone Marrow Failure and Malignant Hemopoietic Clone Control, Tianjin, 300052, China
- Tianjin Institute of Hematology, Tianjin, 300052, China
| | - Hui Liu
- Department of Hematology, Tianjin Medical University General Hospital, 154 Anshan Street, Heping District, Tianjin, 300052, China
- Tianjin Key Laboratory of Bone Marrow Failure and Malignant Hemopoietic Clone Control, Tianjin, 300052, China
- Tianjin Institute of Hematology, Tianjin, 300052, China
| | - Kai Ding
- Department of Hematology, Tianjin Medical University General Hospital, 154 Anshan Street, Heping District, Tianjin, 300052, China
- Tianjin Key Laboratory of Bone Marrow Failure and Malignant Hemopoietic Clone Control, Tianjin, 300052, China
- Tianjin Institute of Hematology, Tianjin, 300052, China
| | - Panpan Cao
- Department of Hematology, Tianjin Medical University General Hospital, 154 Anshan Street, Heping District, Tianjin, 300052, China
- Tianjin Key Laboratory of Bone Marrow Failure and Malignant Hemopoietic Clone Control, Tianjin, 300052, China
- Tianjin Institute of Hematology, Tianjin, 300052, China
| | - Xiaohan Liu
- Department of Hematology, Tianjin Medical University General Hospital, 154 Anshan Street, Heping District, Tianjin, 300052, China
- Tianjin Key Laboratory of Bone Marrow Failure and Malignant Hemopoietic Clone Control, Tianjin, 300052, China
- Tianjin Institute of Hematology, Tianjin, 300052, China
| | - Lijuan Li
- Department of Hematology, Tianjin Medical University General Hospital, 154 Anshan Street, Heping District, Tianjin, 300052, China
- Tianjin Key Laboratory of Bone Marrow Failure and Malignant Hemopoietic Clone Control, Tianjin, 300052, China
- Tianjin Institute of Hematology, Tianjin, 300052, China
| | - Zhaoyun Liu
- Department of Hematology, Tianjin Medical University General Hospital, 154 Anshan Street, Heping District, Tianjin, 300052, China.
- Tianjin Key Laboratory of Bone Marrow Failure and Malignant Hemopoietic Clone Control, Tianjin, 300052, China.
- Tianjin Institute of Hematology, Tianjin, 300052, China.
| | - Rong Fu
- Department of Hematology, Tianjin Medical University General Hospital, 154 Anshan Street, Heping District, Tianjin, 300052, China.
- Tianjin Key Laboratory of Bone Marrow Failure and Malignant Hemopoietic Clone Control, Tianjin, 300052, China.
- Tianjin Institute of Hematology, Tianjin, 300052, China.
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Chen Y, Liu Y, Fu Z, Xu J, Guo L, Cao H, Gan L, Gao S, Liu Y. GalNAc-Conjugated siRNA Targeting Complement C3 Inhibits Osteoclast Activation in Periodontitis. Oral Dis 2025; 31:589-599. [PMID: 39472674 DOI: 10.1111/odi.15170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2024] [Revised: 09/22/2024] [Accepted: 10/09/2024] [Indexed: 04/09/2025]
Abstract
OBJECTIVE The complement cascade plays an important role in the inflammation amplification and tissue destruction of periodontitis. Importantly, complement C3 was proved to be the central element of complement cascade. Thus, targeting inhibition of C3 has become one of the focuses of treatment method development and exploration. METHODS The siRNAs targeting C3 were designed and screened for in vitro potency. The selected siRNA was conjugated to GalNAc (GalNAc-C3 siRNA) for liver-specific delivery. The mouse model of periodontitis was established by silk ligation. Stereomicroscopy, Micro-CT, histological and histochemical assessment, and immunofluorescence staining were performed to evaluate the level of bone destructive and osteoclast activity. The influence of GalNAc-C3 siRNA on inflammatory reactions was determined by qRT-PCR, ELISA, and flow cytometry. RESULTS GalNAc-C3 siRNA showed great in vivo potency and durability to silence hepatic C3 mRNA expression. GalNAc-C3 siRNA treatment could effectively inhibit the production of inflammatory cytokines (IL-17A, TNF-α, IL-6, and IFN-γ) and restrain Th17 differentiation. Importantly, the expression of RANKL and differentiation of osteoclast were inhibited by GalNAc-C3 siRNA. CONCLUSION GalNAc-C3 siRNA could efficiently play a role in bone protection by inhibiting inflammatory responses and osteoclast activities. This therapeutic siRNA may become an effective treatment strategy for periodontitis.
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Affiliation(s)
- Yingyi Chen
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, People's Republic of China
- Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Yitong Liu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, People's Republic of China
- Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Zhongguo Fu
- Suzhou Ribo Life Science co. Ltd., Jiangsu, China
| | - Junji Xu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, People's Republic of China
- Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Lijia Guo
- Department of Orthodontics, School of Stomatology, Capital Medical University, Beijing, People's Republic of China
| | - Huiqing Cao
- Suzhou Ribo Life Science co. Ltd., Jiangsu, China
| | - Liming Gan
- Suzhou Ribo Life Science co. Ltd., Jiangsu, China
- Ribocure Pharmaceuticals AB, Gothenburg, Sweden
| | - Shan Gao
- Suzhou Ribo Life Science co. Ltd., Jiangsu, China
| | - Yi Liu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Beijing, People's Republic of China
- Immunology Research Center for Oral and Systemic Health, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China
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Irfan M, Kim JH, Sreekumar S, Chung S. RNA sequencing reveals key factors modulating TNFα-stimulated odontoblast-like differentiation of dental pulp stem cells. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2025:2025.01.09.632294. [PMID: 39868289 PMCID: PMC11761799 DOI: 10.1101/2025.01.09.632294] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/28/2025]
Abstract
Inflammation is a complex host response to harmful infections or injuries, playing both beneficial and detrimental roles in tissue regeneration. Notably, clinical dentinogenesis associated with caries development occurs within an inflammatory environment. Reparative dentinogenesis is closely linked to intense inflammation, which triggers the recruitment and differentiation of dental pulp stem cells (DPSCs) into the dentin lineage. Understanding how inflammatory responses influence DPSCs is essential for elucidating the mechanisms underlying dentin and pulp regeneration. Given the limited data on this process, a broad approach is employed here to gain a deeper understanding of the complex mechanisms involved and to identify downstream signaling targets. This study aims to investigate the role of inflammation and the complement receptor C5L2 in the odontoblastic differentiation of DPSCs and the associated transcriptomic changes using poly-A RNA sequencing (RNA-seq). RNA-seq techniques provide insight into the transcriptome of a cell, offering higher coverage and greater resolution of its dynamic nature. Following inflammatory stimulation, DPSCs exhibit significantly altered gene profiles, including marked upregulation of key odontogenic genes, highlighting the critical role of inflammation in dentinogenesis. We demonstrate that TNFα-treated odontoblast-like differentiating DPSCs, under C5L2 modulation, exhibit significant differential gene expression and transcriptomic changes. The data presented may provide new avenues for experimental approaches to uncover pathways in dentinogenesis by identifying specific transcription factors and gene profiles.
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Affiliation(s)
- Muhammad Irfan
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago 60612, IL, USA
| | - Ji Hyun Kim
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago 60612, IL, USA
| | - Sreelekshmi Sreekumar
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago 60612, IL, USA
| | - Seung Chung
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago 60612, IL, USA
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Dong Q, Zhou J, Feng M, Kong L, Fang B, Zhang Z. A review of bacterial and osteoclast differentiation in bone infection. Microb Pathog 2024; 197:107102. [PMID: 39505086 DOI: 10.1016/j.micpath.2024.107102] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/29/2024] [Revised: 10/18/2024] [Accepted: 11/03/2024] [Indexed: 11/08/2024]
Abstract
Bone infections are characterized by bacterial invasion of the bone microenvironment and subsequent bone structure deterioration. This holds significance because osteoclasts, which are the only cells responsible for bone resorption, are abnormally stimulated during bone infections. Multiple communication factors secreted by bone stromal cells regulate the membrane of osteoclast progenitor cells, thereby maintaining bone homeostasis through the expression of many types of receptors. During infection, the immunoinflammatory response triggered by bacterial invasion and multiple virulence factors of bacterial origin can disrupt osteoclast homeostasis. Therefore, clarifying the pathways through which bacteria affect osteoclasts can offer a theoretical basis for preventing and treating bone infections. This review summarizes studies investigating bone destruction caused by different bacterial infections. In conclusion, bacteria can affect osteoclast metabolic activity through multiple pathways, including direct contact, release of virulence factors, induction of immunoinflammatory responses, influence on bone stromal cell metabolism, and intracellular infections.
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Affiliation(s)
- Qi Dong
- Department of Spinal Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710054, China
| | - Jiuqin Zhou
- Department of Infectious Disease of Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710054, China
| | - Mingzhe Feng
- Department of Spinal Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710054, China
| | - Lingqiang Kong
- Department of Orthopedics, the Central Hospital Affiliated to Shaoxing University, Shaoxing, 312030, China.
| | - Bin Fang
- Department of Orthopedics, the First Affiliated Hospital of Zhejiang Chinese Medical University (Zhejiang Provincial Hospital of Chinese Medicine), Hangzhou, 310000, China.
| | - Zhen Zhang
- Department of Spinal Surgery, Honghui Hospital, Xi'an Jiaotong University, Xi'an, 710054, China.
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10
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Liao Z, Zheng X, Li H, Deng Z, Feng S, Tan H, Zhao L. Carboxypeptidase M modulates BMSCs osteogenesis-adipogenesis via the MAPK/ERK pathway: An integrated single-cell and bulk transcriptomic study. FASEB J 2024; 38:e23657. [PMID: 38713087 DOI: 10.1096/fj.202302508r] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2023] [Revised: 04/16/2024] [Accepted: 04/25/2024] [Indexed: 05/08/2024]
Abstract
The pathogenesis of osteoporosis (OP) is closely associated with the disrupted balance between osteogenesis and adipogenesis in bone marrow-derived mesenchymal stem cells (BMSCs). We analyzed published single-cell RNA sequencing (scRNA-seq) data to dissect the transcriptomic profiles of bone marrow-derived cells in OP, reviewing 56 377 cells across eight scRNA-seq datasets from femoral heads (osteoporosis or osteopenia n = 5, osteoarthritis n = 3). Seventeen genes, including carboxypeptidase M (CPM), were identified as key osteogenesis-adipogenesis regulators through comprehensive gene set enrichment, differential expression, regulon activity, and pseudotime analyses. In vitro, CPM knockdown reduced osteogenesis and promoted adipogenesis in BMSCs, while adenovirus-mediated CPM overexpression had the reverse effects. In vivo, intraosseous injection of CPM-overexpressing BMSCs mitigated bone loss in ovariectomized mice. Integrated scRNA-seq and bulk RNA sequencing analyses provided insight into the MAPK/ERK pathway's role in the CPM-mediated regulation of BMSC osteogenesis and adipogenesis; specifically, CPM overexpression enhanced MAPK/ERK signaling and osteogenesis. In contrast, the ERK1/2 inhibitor binimetinib negated the effects of CPM overexpression. Overall, our findings identify CPM as a pivotal regulator of BMSC differentiation, which provides new clues for the mechanistic study of OP.
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Affiliation(s)
- Zheting Liao
- Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Xiaoyong Zheng
- Orthopaedic Department, The 4th Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Hongfang Li
- Beijing Yijiandian Clinic, Beijing, China
- Health Management Center, Peking University International Hospital, Beijing, China
| | - Zhonghao Deng
- Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Shuhao Feng
- Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Hongbo Tan
- Department of Orthopaedic, The 920th Hospital of Joint Logistics Support Force, Kunming, Yunnan, China
| | - Liang Zhao
- Department of Orthopedics, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
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11
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Ruths L, Huber-Lang M, Schulze-Tanzil G, Riegger J. Anaphylatoxins and their corresponding receptors as potential drivers in cartilage calcification during osteoarthritis progression. Osteoarthritis Cartilage 2024; 32:514-525. [PMID: 38242312 DOI: 10.1016/j.joca.2024.01.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 01/08/2024] [Accepted: 01/12/2024] [Indexed: 01/21/2024]
Abstract
OBJECTIVE The complement cascade as major fluid phase innate immune system is activated during progression of osteoarthritis (OA). Generated anaphylatoxins and the corresponding receptors C3aR and C5aR1 are associated with the calcification of blood vessels and involved in osteogenic differentiation. This study aims on elucidating whether complement activation products contribute to cartilage calcification of OA cartilage. METHOD Human articular chondrocytes were osteogenically differentiated in vitro in the presence or absence of C3a, C5a, and bone morphogenetic protein (BMP) 2. Furthermore, macroscopically intact (OARSI grade ≤ 1) and highly degenerated human cartilage (OARSI grade ≥ 3) was used for C3aR and C5aR1 histochemistry. Calcification of the cartilage was assessed by Alizarin Red S and von Kossa staining. RESULTS C3a and C5a amplified matrix mineralization during in vitro osteogenesis, while inhibition of the corresponding receptors impaired calcium deposition. Moreover, C3aR and C5aR1 expression was upregulated during osteogenic differentiation and also in degenerated cartilage. Additionally, anaphylatoxin receptor expression was positively associated with calcification of native cartilage tissue and calcium deposition during osteogenic differentiation. Finally, the pro-hypertrophic growth factor BMP2 induced the expression of C5aR1. CONCLUSIONS Our findings indicate that anaphylatoxins and their receptors play a decisive role in cartilage calcification processes during OA progression.
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Affiliation(s)
- Leonie Ruths
- Division for Biochemistry of Joint and Connective Tissue Diseases, University Hospital Ulm, Ulm, Germany
| | - Markus Huber-Lang
- Institute of Clinical and Experimental Trauma Immunology, University Hospital Ulm, Ulm, Germany
| | - Gundula Schulze-Tanzil
- Department of Anatomy and Cell Biology, Paracelsus Medical University, Nuremberg, Germany
| | - Jana Riegger
- Division for Biochemistry of Joint and Connective Tissue Diseases, University Hospital Ulm, Ulm, Germany
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12
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Daponte V, Henke K, Drissi H. Current perspectives on the multiple roles of osteoclasts: Mechanisms of osteoclast-osteoblast communication and potential clinical implications. eLife 2024; 13:e95083. [PMID: 38591777 PMCID: PMC11003748 DOI: 10.7554/elife.95083] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2023] [Accepted: 03/29/2024] [Indexed: 04/10/2024] Open
Abstract
Bone remodeling is a complex process involving the coordinated actions of osteoblasts and osteoclasts to maintain bone homeostasis. While the influence of osteoblasts on osteoclast differentiation is well established, the reciprocal regulation of osteoblasts by osteoclasts has long remained enigmatic. In the past few years, a fascinating new role for osteoclasts has been unveiled in promoting bone formation and facilitating osteoblast migration to the remodeling sites through a number of different mechanisms, including the release of factors from the bone matrix following bone resorption and direct cell-cell interactions. Additionally, considerable evidence has shown that osteoclasts can secrete coupling factors known as clastokines, emphasizing the crucial role of these cells in maintaining bone homeostasis. Due to their osteoprotective function, clastokines hold great promise as potential therapeutic targets for bone diseases. However, despite long-standing work to uncover new clastokines and their effect in vivo, more substantial efforts are still required to decipher the mechanisms and pathways behind their activity in order to translate them into therapies. This comprehensive review provides insights into our evolving understanding of the osteoclast function, highlights the significance of clastokines in bone remodeling, and explores their potential as treatments for bone diseases suggesting future directions for the field.
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Affiliation(s)
- Valentina Daponte
- Department of Orthopaedics, Emory University School of MedicineAtlantaUnited States
- VA Medical CenterAtlantaUnited States
| | - Katrin Henke
- Department of Orthopaedics, Emory University School of MedicineAtlantaUnited States
| | - Hicham Drissi
- Department of Orthopaedics, Emory University School of MedicineAtlantaUnited States
- VA Medical CenterAtlantaUnited States
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13
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Heggli I, Teixeira GQ, Iatridis JC, Neidlinger‐Wilke C, Dudli S. The role of the complement system in disc degeneration and Modic changes. JOR Spine 2024; 7:e1312. [PMID: 38312949 PMCID: PMC10835744 DOI: 10.1002/jsp2.1312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Revised: 12/15/2023] [Accepted: 01/04/2024] [Indexed: 02/06/2024] Open
Abstract
Disc degeneration and vertebral endplate bone marrow lesions called Modic changes are prevalent spinal pathologies found in chronic low back pain patients. Their pathomechanisms are complex and not fully understood. Recent studies have revealed that complement system proteins and interactors are dysregulated in disc degeneration and Modic changes. The complement system is part of the innate immune system and plays a critical role in tissue homeostasis. However, its dysregulation has also been associated with various pathological conditions such as rheumatoid arthritis and osteoarthritis. Here, we review the evidence for the involvement of the complement system in intervertebral disc degeneration and Modic changes. We found that only a handful of studies reported on complement factors in Modic changes and disc degeneration. Therefore, the level of evidence for the involvement of the complement system is currently low. Nevertheless, the complement system is tightly intertwined with processes known to occur during disc degeneration and Modic changes, such as increased cell death, autoantibody production, bacterial defense processes, neutrophil activation, and osteoclast formation, indicating a contribution of the complement system to these spinal pathologies. Based on these mechanisms, we propose a model how the complement system could contribute to the vicious cycle of tissue damage and chronic inflammation in disc degeneration and Modic changes. With this review, we aim to highlight a currently understudied but potentially important inflammatory pathomechanism of disc degeneration and Modic changes that may be a novel therapeutic target.
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Affiliation(s)
- Irina Heggli
- Center of Experimental Rheumatology, Department of RheumatologyUniversity Hospital Zurich, University of ZurichZurichSwitzerland
- Department of Physical Medicine and RheumatologyBalgrist University Hospital, Balgrist Campus, University of ZurichZurichSwitzerland
- Leni and Peter W. May Department of OrthopaedicsIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | - Graciosa Q. Teixeira
- Institute of Orthopedic Research and Biomechanics, Trauma Research Centre, Ulm UniversityUlmGermany
| | - James C. Iatridis
- Leni and Peter W. May Department of OrthopaedicsIcahn School of Medicine at Mount SinaiNew YorkNew YorkUSA
| | | | - Stefan Dudli
- Center of Experimental Rheumatology, Department of RheumatologyUniversity Hospital Zurich, University of ZurichZurichSwitzerland
- Department of Physical Medicine and RheumatologyBalgrist University Hospital, Balgrist Campus, University of ZurichZurichSwitzerland
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14
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Tjandra PM, Ripplinger CM, Christiansen BA. The heart-bone connection: relationships between myocardial infarction and osteoporotic fracture. Am J Physiol Heart Circ Physiol 2024; 326:H845-H856. [PMID: 38305753 PMCID: PMC11062618 DOI: 10.1152/ajpheart.00576.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2023] [Revised: 01/22/2024] [Accepted: 01/23/2024] [Indexed: 02/03/2024]
Abstract
Myocardial infarction (MI) and osteoporotic fracture (Fx) are two of the leading causes of mortality and morbidity worldwide. Although these traumatic injuries are treated as if they are independent, there is epidemiological evidence linking the incidence of Fx and MI, thus raising the question of whether each of these events can actively influence the risk of the other. Atherosclerotic cardiovascular disease and osteoporosis, the chronic conditions leading to MI and Fx, are known to have shared pathoetiology. Furthermore, sustained systemic inflammation after traumas such as MI and Fx has been shown to exacerbate both underlying chronic conditions. However, the effects of MI and Fx outside their own system have not been well studied. The sympathetic nervous system (SNS) and the complement system initiate a systemic response after MI that could lead to subsequent changes in bone remodeling through osteoclasts. Similarly, SNS and complement system activation following fracture could lead to heart tissue damage and exacerbate atherosclerosis. To determine whether damaging bone-heart cross talk may be important comorbidity following Fx or MI, this review details the current understanding of bone loss after MI, cardiovascular damage after Fx, and possible shared underlying mechanisms of these processes.
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Affiliation(s)
- Priscilla M Tjandra
- Department of Orthopaedic Surgery, University of California San Francisco, San Francisco, California, United States
- Biomedical Engineering Graduate Group, University of California Davis, Davis, California, United States
| | - Crystal M Ripplinger
- Biomedical Engineering Graduate Group, University of California Davis, Davis, California, United States
- Department of Pharmacology, University of California Davis Health, Davis, California, United States
| | - Blaine A Christiansen
- Biomedical Engineering Graduate Group, University of California Davis, Davis, California, United States
- Department of Orthopaedic Surgery, University of California Davis Health, Sacramento, California, United States
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15
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Irfan M, Marzban H, Chung S. C5L2 CRISPR KO enhances dental pulp stem cell-mediated dentinogenesis via TrkB under TNFα-induced inflammation. Front Cell Dev Biol 2024; 12:1338419. [PMID: 38318114 PMCID: PMC10839780 DOI: 10.3389/fcell.2024.1338419] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2023] [Accepted: 01/04/2024] [Indexed: 02/07/2024] Open
Abstract
Background and Objectives: Dental caries is one of the most common human pathological conditions resulting from the invasion of bacteria into the dentin. Current treatment options are limited. In many cases, endodontic therapy leads to permanent pulp tissue loss. Dentin-pulp complex regeneration involves dental pulp stem cells (DPSCs) that differentiate into odontoblast-like cells under an inflammatory context. However, limited information is available on how DPSC differentiation processes are affected under inflammatory environments. We identified the crucial role of complement C5a and its receptor C5aR in the inflammation-induced odontoblastic DPSC differentiation. Methodology: Here, we further investigated the role of a second and controversial C5a receptor, C5L2, in this process and explored the underlying mechanism. Human DPSCs were examined during 7-, 10-, and 14-day odontogenic differentiation treated with TNFα, C5L2 CRISPR, and tyrosine receptor kinase B (TrkB) antagonist [cyclotraxin-B (CTX-B)]. Results: Our data demonstrate that C5L2 CRISPR knockout (KO) enhances mineralization in TNFα-stimulated differentiating DPSCs. We further confirmed that C5L2 CRISPR KO significantly enhances dentin sialophosphoprotein (DSPP) and dentin matrix protein-1 (DMP-1) expression after 14-day odontoblastic DPSC differentiation, and treatment with CTX-B abolished the TNFα/C5L2 CRISPR KO-induced DSPP and DMP-1 increase, suggesting TrkB's critical role in this process. Conclusion and Key applications: Our data suggest a regulatory role of C5L2 and TrkB in the TNFα-induced odontogenic DPSC differentiation. This study may provide a useful tool to understand the mechanisms of the role of inflammation in dentinogenesis that is required for successful DPSC engineering strategies.
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Affiliation(s)
- Muhammad Irfan
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago, IL, United States
| | - Hassan Marzban
- Department of Human Anatomy and Cell Science, University of Manitoba, Winnipeg, MB, Canada
| | - Seung Chung
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, Chicago, IL, United States
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16
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Meng Q, Wang Y, Yuan T, Su Y, Li Z, Sun S. Osteoclast: The novel whistleblower in osteonecrosis of the femoral head. GENE REPORTS 2023; 33:101833. [DOI: 10.1016/j.genrep.2023.101833] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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17
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Liu A, Chen Z, Li X, Xie C, Chen Y, Su X, Chen Y, Zhang M, Chen J, Yang T, Shen J, Huang H. C5a-C5aR1 induces endoplasmic reticulum stress to accelerate vascular calcification via PERK-eIF2α-ATF4-CREB3L1 pathway. Cardiovasc Res 2023; 119:2563-2578. [PMID: 37603848 DOI: 10.1093/cvr/cvad133] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 04/13/2023] [Accepted: 05/02/2023] [Indexed: 08/23/2023] Open
Abstract
AIMS Vascular calcification (VC) predicts the morbidity and mortality in cardiovascular diseases. Vascular smooth muscle cells (VSMCs) osteogenic transdifferentiation is the crucial pathological basis for VC. To date, the molecular pathogenesis is still largely unclear. Notably, C5a-C5aR1 contributes to the development of cardiovascular diseases, and its closely related to physiological bone mineralization which is similar to VSMCs osteogenic transdifferentiation. However, the role and underlying mechanisms of C5a-C5aR1 in VC remain unexplored. METHODS AND RESULTS A cross-sectional clinical study was utilized to examine the association between C5a and VC. Chronic kidney diseases mice and calcifying VSMCs models were established to investigate the effect of C5a-C5aR1 in VC, evaluated by changes in calcium deposition and osteogenic markers. The cross-sectional study identified that high level of C5a was associated with increased risk of VC. C5a dose-responsively accelerated VSMCs osteogenic transdifferentiation accompanying with increased the expression of C5aR1. Meanwhile, the antagonists of C5aR1, PMX 53, reduced calcium deposition, and osteogenic transdifferentiation both in vivo and in vitro. Mechanistically, C5a-C5aR1 induced endoplasmic reticulum (ER) stress and then activated PERK-eIF2α-ATF4 pathway to accelerated VSMCs osteogenic transdifferentiation. In addition, cAMP-response element-binding protein 3-like 1 (CREB3L1) was a key downstream mediator of PERK-eIF2α-ATF4 pathway which accelerated VSMCs osteogenic transdifferentiation by promoting the expression of COL1α1. CONCLUSIONS High level of C5a was associated with increased risk of VC, and it accelerated VC by activating the receptor C5aR1. PERK-eIF2α-ATF4-CREB3L1 pathway of ER stress was activated by C5a-C5aR1, hence promoting VSMCs osteogenic transdifferentiation. Targeting C5 or C5aR1 may be an appealing therapeutic target for VC.
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Affiliation(s)
- Aiting Liu
- Department of Cardiology, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, The Eighth Affiliated Hospital of Sun Yat-sen University, Shennan Middle Rd, Shenzhen, 518000, China
| | - Zhenwei Chen
- Department of Nephrology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518000, China
| | - Xiaoxue Li
- Department of Cardiology, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, The Eighth Affiliated Hospital of Sun Yat-sen University, Shennan Middle Rd, Shenzhen, 518000, China
| | - Chen Xie
- Department of Cardiology, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, The Eighth Affiliated Hospital of Sun Yat-sen University, Shennan Middle Rd, Shenzhen, 518000, China
| | - Yanlian Chen
- Department of Cardiology, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, The Eighth Affiliated Hospital of Sun Yat-sen University, Shennan Middle Rd, Shenzhen, 518000, China
| | - Xiaoyan Su
- Department of Nephropathy, Tungwah Hospital of Sun Yat-Sen University, Dongguan, 523000, China
| | - Ying Chen
- Department of Nephropathy, Tungwah Hospital of Sun Yat-Sen University, Dongguan, 523000, China
| | - Mengbi Zhang
- Department of Nephropathy, Tungwah Hospital of Sun Yat-Sen University, Dongguan, 523000, China
| | - Jie Chen
- Department of Radiotherapy, Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, 510000, China
| | - Tiecheng Yang
- Department of Nephrology, The Eighth Affiliated Hospital of Sun Yat-sen University, Shenzhen, 518000, China
| | - Jiangang Shen
- School of Chinese Medicine, Li Ka Shing Faculty of Medicine, State Key Laboratory of Pharmaceutical Biotechnology, The University of Hong Kong, Hong Kong, 999077, China
| | - Hui Huang
- Department of Cardiology, Joint Laboratory of Guangdong-Hong Kong-Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases, The Eighth Affiliated Hospital of Sun Yat-sen University, Shennan Middle Rd, Shenzhen, 518000, China
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18
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Schanzenbacher J, Hendrika Kähler K, Mesler E, Kleingarn M, Marcel Karsten C, Leonard Seiler D. The role of C5a receptors in autoimmunity. Immunobiology 2023; 228:152413. [PMID: 37598588 DOI: 10.1016/j.imbio.2023.152413] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2023] [Revised: 06/04/2023] [Accepted: 06/10/2023] [Indexed: 08/22/2023]
Abstract
The complement system is an essential component of the innate immune response and plays a vital role in host defense and inflammation. Dysregulation of the complement system, particularly involving the anaphylatoxin C5a and its receptors (C5aR1 and C5aR2), has been linked to several autoimmune diseases, indicating the potential for targeted therapies. C5aR1 and C5aR2 are seven-transmembrane receptors with distinct signaling mechanisms that play both partially overlapping and opposing roles in immunity. Both receptors are expressed on a broad spectrum of immune and non-immune cells and are involved in cellular functions and physiological processes during homeostasis and inflammation. Dysregulated C5a-mediated inflammation contributes to autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus, multiple sclerosis, epidermolysis bullosa acquisita, antiphospholipid syndrome, and others. Therefore, targeting C5a or its receptors may yield therapeutic innovations in these autoimmune diseases by reducing the recruitment and activation of immune cells that lead to tissue inflammation and injury, thereby exacerbating the autoimmune response. Clinical trials focused on the inhibition of C5 cleavage or the C5a/C5aR1-axis using small molecules or monoclonal antibodies hold promise for bringing novel treatments for autoimmune diseases into practice. However, given the heterogeneous nature of (systemic) autoimmune diseases, there are still several challenges, such as patient selection, optimal dosing, and treatment duration, that require further investigation and development to realize the full therapeutic potential of C5a receptor inhibition, ideally in the context of a personalized medicine approach. Here, we aim to provide a brief overview of the current knowledge on the function of C5a receptors, the involvement of C5a receptors in autoimmune disorders, the molecular mechanisms underlying C5a receptor-mediated autoimmunity, and the potential for targeted therapies to modulate their activity.
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Affiliation(s)
- Jovan Schanzenbacher
- Institute for Systemic Inflammation Research (ISEF), University of Lübeck, Lübeck, Germany
| | - Katja Hendrika Kähler
- Institute for Systemic Inflammation Research (ISEF), University of Lübeck, Lübeck, Germany
| | - Evelyn Mesler
- Institute for Systemic Inflammation Research (ISEF), University of Lübeck, Lübeck, Germany
| | - Marie Kleingarn
- Institute for Systemic Inflammation Research (ISEF), University of Lübeck, Lübeck, Germany
| | | | - Daniel Leonard Seiler
- Institute for Systemic Inflammation Research (ISEF), University of Lübeck, Lübeck, Germany.
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19
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Harris VK, Wollowitz J, Greenwald J, Carlson AL, Sadiq SA. Mesenchymal stem cell-neural progenitors are enriched in cell signaling molecules implicated in their therapeutic effect in multiple sclerosis. PLoS One 2023; 18:e0290069. [PMID: 37566599 PMCID: PMC10420335 DOI: 10.1371/journal.pone.0290069] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2023] [Accepted: 08/01/2023] [Indexed: 08/13/2023] Open
Abstract
Mesenchymal stem cell-neural progenitors (MSC-NP) are a neural derivative of MSCs that are being investigated in clinical trials as an autologous intrathecal cell therapy to treat patients with secondary progressive (SP) or primary progressive (PP) multiple sclerosis (MS). MSC-NPs promote tissue repair through paracrine mechanisms, however which secreted factors mediate the therapeutic potential of MSC-NPs and how this cell population differs from MSCs remain poorly understood. The objective of this study was to define the transcriptional profile of MSCs and MSC-NPs from MS and non-MS donors to better characterize each cell population. MSCs derived from SPMS, PPMS, or non-MS bone marrow donors demonstrated minimal differential gene expression, despite differences in disease status. MSC-NPs from both MS and non-MS-donors exhibited significant differential gene expression compared to MSCs, with 2,156 and 1,467 genes upregulated and downregulated, respectively. Gene ontology analysis demonstrated pronounced downregulation of cell cycle genes in MSC-NPs compared to MSC consistent with reduced proliferation of MSC-NPs in vitro. In addition, MSC-NPs demonstrated significant enrichment of genes involved in cell signaling, cell communication, neuronal differentiation, chemotaxis, migration, and complement activation. These findings suggest that increased cell signaling and chemotactic capability of MSC-NPs may support their therapeutic potential in MS.
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Affiliation(s)
- Violaine K. Harris
- Tisch Multiple Sclerosis Research Center of New York, New York, New York, United States of America
| | - Jaina Wollowitz
- Tisch Multiple Sclerosis Research Center of New York, New York, New York, United States of America
| | - Jacelyn Greenwald
- Tisch Multiple Sclerosis Research Center of New York, New York, New York, United States of America
| | - Alyssa L. Carlson
- Tisch Multiple Sclerosis Research Center of New York, New York, New York, United States of America
| | - Saud A. Sadiq
- Tisch Multiple Sclerosis Research Center of New York, New York, New York, United States of America
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20
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Lopes VR, Birgersson U, Manivel VA, Hulsart-Billström G, Gallinetti S, Aparicio C, Hong J. Human Whole Blood Interactions with Craniomaxillofacial Reconstruction Materials: Exploring In Vitro the Role of Blood Cascades and Leukocytes in Early Healing Events. J Funct Biomater 2023; 14:361. [PMID: 37504856 PMCID: PMC10381968 DOI: 10.3390/jfb14070361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2023] [Revised: 07/03/2023] [Accepted: 07/05/2023] [Indexed: 07/29/2023] Open
Abstract
The present study investigated early interactions between three alloplastic materials (calcium phosphate (CaP), titanium alloy (Ti), and polyetheretherketone (PEEK) with human whole blood using an established in vitro slide chamber model. After 60 min of contact with blood, coagulation (thrombin-antithrombin complexes, TAT) was initiated on all test materials (Ti > PEEK > CaP), with a significant increase only for Ti. All materials showed increased contact activation, with the KK-AT complex significantly increasing for CaP (p < 0.001), Ti (p < 0.01), and PEEK (p < 0.01) while only CaP demonstrated a notable rise in KK-C1INH production (p < 0.01). The complement system had significant activation across all materials, with CaP (p < 0.0001, p < 0.0001) generating the most pronounced levels of C3a and sC5b-9, followed by Ti (p < 0.001, p < 0.001) and lastly, PEEK (p < 0.001, p < 0.01). This activation correlated with leukocyte stimulation, particularly myeloperoxidase release. Consequently, the complement system may assume a more significant role in the early stages post implantation in response to CaP materials than previously recognized. Activation of the complement system and the inevitable activation of leukocytes might provide a more favorable environment for tissue remodeling and repair than has been traditionally acknowledged. While these findings are limited to the early blood response, complement and leukocyte activation suggest improved healing outcomes, which may impact long-term clinical outcomes.
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Affiliation(s)
- Viviana R Lopes
- OssDsign AB, SE-754 50 Uppsala, Sweden
- Department of Medicinal Chemistry, Translational Imaging, Uppsala University, SE-751 83 Uppsala, Sweden
| | - Ulrik Birgersson
- Department of Clinical Science, Intervention and Technology, Division of Imaging and Technology, Karolinska Institute, SE-141 52 Huddinge, Sweden
- Department of Clinical Neuroscience, Neurosurgical Section, Karolinska University Hospital, SE-171 77 Stockholm, Sweden
| | - Vivek Anand Manivel
- Rudbeck Laboratory, Department of Immunology, Genetics and Pathology (IGP), Uppsala University, SE-751 85 Uppsala, Sweden
| | - Gry Hulsart-Billström
- Department of Medicinal Chemistry, Translational Imaging, Uppsala University, SE-751 83 Uppsala, Sweden
| | - Sara Gallinetti
- OssDsign AB, SE-754 50 Uppsala, Sweden
- Department of Engineering Sciences, Applied Materials Science Section, Uppsala University, SE-751 03 Uppsala, Sweden
| | - Conrado Aparicio
- Faculty of Odontology, UIC Barcelona-International University of Catalonia, 08195 Barcelona, Spain
- IBEC-Institute for Bioengineering of Catalonia, 08028 Barcelona, Spain
| | - Jaan Hong
- Rudbeck Laboratory, Department of Immunology, Genetics and Pathology (IGP), Uppsala University, SE-751 85 Uppsala, Sweden
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21
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Kuhn MB, VandenBerg HS, Reynolds AJ, Carson MD, Warner AJ, LaRue AC, Novince CM, Hathaway-Schrader JD. C3a-C3aR signaling is a novel modulator of skeletal homeostasis. Bone Rep 2023; 18:101662. [PMID: 36860797 PMCID: PMC9969257 DOI: 10.1016/j.bonr.2023.101662] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/10/2022] [Revised: 02/13/2023] [Accepted: 02/15/2023] [Indexed: 02/18/2023] Open
Abstract
Osteoimmune studies have identified complement signaling as an important regulator of the skeleton. Specifically, complement anaphylatoxin receptors (i.e., C3aR, C5aR) are expressed on osteoblasts and osteoclasts, implying that C3a and/or C5a may be candidate mediators of skeletal homeostasis. The study aimed to determine how complement signaling influences bone modeling/remodeling in the young skeleton. Female C57BL/6J C3aR-/-C5aR-/- vs. wildtype and C3aR-/- vs. wildtype mice were examined at age 10 weeks. Trabecular and cortical bone parameters were analyzed by micro-CT. In situ osteoblast and osteoclast outcomes were determined by histomorphometry. Osteoblast and osteoclast precursors were assessed in vitro. C3aR-/-C5aR-/- mice displayed an increased trabecular bone phenotype at age 10 weeks. In vitro studies revealed C3aR-/-C5aR-/- vs. wildtype cultures had less bone-resorbing osteoclasts and increased bone-forming osteoblasts, which were validated in vivo. To determine whether C3aR alone was critical for the enhanced skeletal outcomes, wildtype vs. C3aR-/- mice were evaluated for osseous tissue outcomes. Paralleling skeletal findings in C3aR-/-C5aR-/- mice, C3aR-/- vs. wildtype mice had an enhanced trabecular bone volume fraction, which was attributed to increased trabecular number. There was elevated osteoblast activity and suppressed osteoclastic cells in C3aR-/- vs. wildtype mice. Furthermore, primary osteoblasts derived from wildtype mice were stimulated with exogenous C3a, which more profoundly upregulated C3ar1 and the pro-osteoclastic chemokine Cxcl1. This study introduces the C3a/C3aR signaling axis as a novel regulator of the young skeleton.
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Affiliation(s)
- Megan B. Kuhn
- Department of Oral Health Sciences, College of Dental Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Hayden S. VandenBerg
- Department of Oral Health Sciences, College of Dental Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Andrew J. Reynolds
- Department of Oral Health Sciences, College of Dental Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Matthew D. Carson
- Department of Oral Health Sciences, College of Dental Medicine, Medical University of South Carolina, Charleston, SC, USA
- Department of Stomatology-Div. of Periodontics, College of Dental Medicine, Medical University of South Carolina, Charleston, SC, USA
- Department of Pediatrics-Div. of Endocrinology, College of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Amy J. Warner
- Department of Oral Health Sciences, College of Dental Medicine, Medical University of South Carolina, Charleston, SC, USA
- Department of Stomatology-Div. of Periodontics, College of Dental Medicine, Medical University of South Carolina, Charleston, SC, USA
- Department of Pediatrics-Div. of Endocrinology, College of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Amanda C. LaRue
- Research Services, Ralph H. Johnson Department of Veterans Affairs Health Care System, Charleston, SC, USA
- Department of Pathology and Laboratory Medicine, College of Medicine, Medical University of South Carolina, Charleston, SC, USA
- Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
| | - Chad M. Novince
- Department of Oral Health Sciences, College of Dental Medicine, Medical University of South Carolina, Charleston, SC, USA
- Department of Stomatology-Div. of Periodontics, College of Dental Medicine, Medical University of South Carolina, Charleston, SC, USA
- Department of Pediatrics-Div. of Endocrinology, College of Medicine, Medical University of South Carolina, Charleston, SC, USA
| | - Jessica D. Hathaway-Schrader
- Department of Stomatology-Div. of Periodontics, College of Dental Medicine, Medical University of South Carolina, Charleston, SC, USA
- Research Services, Ralph H. Johnson Department of Veterans Affairs Health Care System, Charleston, SC, USA
- Department of Pathology and Laboratory Medicine, College of Medicine, Medical University of South Carolina, Charleston, SC, USA
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22
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Ghosh M, Rana S. The anaphylatoxin C5a: Structure, function, signaling, physiology, disease, and therapeutics. Int Immunopharmacol 2023; 118:110081. [PMID: 36989901 DOI: 10.1016/j.intimp.2023.110081] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Revised: 03/06/2023] [Accepted: 03/21/2023] [Indexed: 03/30/2023]
Abstract
The complement system is one of the oldest known tightly regulated host defense systems evolved for efficiently functioning cell-based immune systems and antibodies. Essentially, the complement system acts as a pivot between the innate and adaptive arms of the immune system. The complement system collectively represents a cocktail of ∼50 cell-bound/soluble glycoproteins directly involved in controlling infection and inflammation. Activation of the complement cascade generates complement fragments like C3a, C4a, and C5a as anaphylatoxins. C5a is the most potent proinflammatory anaphylatoxin, which is involved in inflammatory signaling in a myriad of tissues. This review provides a comprehensive overview of human C5a in the context of its structure and signaling under several pathophysiological conditions, including the current and future therapeutic applications targeting C5a.
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Affiliation(s)
- Manaswini Ghosh
- Chemical Biology Laboratory, School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Odisha 752050, India
| | - Soumendra Rana
- Chemical Biology Laboratory, School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Odisha 752050, India.
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23
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Liu A, Luo P, Huang H. New insight of complement system in the process of vascular calcification. J Cell Mol Med 2023; 27:1168-1178. [PMID: 37002701 PMCID: PMC10148053 DOI: 10.1111/jcmm.17732] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2022] [Revised: 03/10/2023] [Accepted: 03/14/2023] [Indexed: 04/03/2023] Open
Abstract
The complement system defences against pathogenic microbes and modulates immune homeostasis by interacting with the innate and adaptive immune systems. Dysregulation, impairment or inadvertent activation of complement system contributes to the pathogenesis of some autoimmune diseases and cardiovascular diseases (CVD). Vascular calcification is the pivotal pathological basis of CVD, and contributes to the high morbidity and mortality of CVD. Increasing evidences indicate that the complement system plays a key role in chronic kidney diseases, atherosclerosis, diabetes mellitus and aging-related diseases, which are closely related with vascular calcification. However, the effect of complement system on vascular calcification is still unclear. In this review, we summarize current evidences about the activation of complement system in vascular calcification. We also describe the complex network of complement system and vascular smooth muscle cells osteogenic transdifferentiation, systemic inflammation, endoplasmic reticulum stress, extracellular matrix remodelling, oxidative stress, apoptosis in vascular calcification. Hence, providing a better understanding of the potential relationship between complement system and vascular calcification, so as to provide a direction for slowing the progression of this burgeoning health concern.
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Affiliation(s)
- Aiting Liu
- Department of Cardiology, The Eighth Affiliated Hospital, Joint Laboratory of Guangdong‐Hong Kong‐Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases Sun Yat‐sen University Shenzhen China
| | - Pei Luo
- State Key Laboratory for Quality Research in Chinese Medicines Macau University of Science and Technology Macau China
| | - Hui Huang
- Department of Cardiology, The Eighth Affiliated Hospital, Joint Laboratory of Guangdong‐Hong Kong‐Macao Universities for Nutritional Metabolism and Precise Prevention and Control of Major Chronic Diseases Sun Yat‐sen University Shenzhen China
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24
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Kuhn A, Riegger J, Teixeira GQ, Huber-Lang M, Lambris JD, Neidlinger-Wilke C, Brenner RE. Terminal Complement Activation Is Induced by Factors Released from Endplate Tissue of Disc Degeneration Patients and Stimulates Expression of Catabolic Enzymes in Annulus Fibrosus Cells. Cells 2023; 12:cells12060887. [PMID: 36980228 PMCID: PMC10047197 DOI: 10.3390/cells12060887] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/07/2023] [Accepted: 03/09/2023] [Indexed: 03/17/2023] Open
Abstract
Terminal complement complex (TCC) deposition was identified in human degenerated discs. To clarify the role of terminal complement activation in disc degeneration (DD), we investigated respective activating mechanisms and cellular effects in annulus fibrosus (AF) cells. Isolated cells from human AF, nucleus pulposus (NP), and endplate (EP) were stimulated with human serum alone or with zymosan and treated with either the C3 inhibitor Cp40 or the C5 antibody eculizumab. Complement activation was determined via anaphylatoxin generation and TCC deposition detection. Thereby, induced catabolic effects were evaluated in cultured AF cells. Moreover, C5 cleavage under degenerative conditions in the presence of AF cells was assessed. Zymosan-induced anaphylatoxin generation and TCC deposition was significantly suppressed by both complement inhibitors. Zymosan induced gene expression of ADAMTS4, MMP1, and COX2. Whereas the C3 blockade attenuated the expression of ADAMTS4, the C5 blockade reduced the expression of ADAMTS4, MMP1, and COX2. Direct C5 cleavage was significantly enhanced by EP conditioned medium from DD patients and CTSD. These results indicate that terminal complement activation might be functionally involved in the progression of DD. Moreover, we found evidence that soluble factors secreted by degenerated EP tissue can mediate direct C5 cleavage, thereby contributing to complement activation in degenerated discs.
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Affiliation(s)
- Amelie Kuhn
- Division for Biochemistry of Joint and Connective Tissue Diseases, Department of Orthopedics, Ulm University, 89081 Ulm, Germany
| | - Jana Riegger
- Division for Biochemistry of Joint and Connective Tissue Diseases, Department of Orthopedics, Ulm University, 89081 Ulm, Germany
| | - Graciosa Q. Teixeira
- Institute of Orthopedic Research and Biomechanics, Trauma Research Centre, Ulm University, 89081 Ulm, Germany
| | - Markus Huber-Lang
- Institute of Clinical and Experimental Trauma Immunology, University Hospital Ulm, 89081 Ulm, Germany
| | - John D. Lambris
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Cornelia Neidlinger-Wilke
- Institute of Orthopedic Research and Biomechanics, Trauma Research Centre, Ulm University, 89081 Ulm, Germany
| | - Rolf E. Brenner
- Division for Biochemistry of Joint and Connective Tissue Diseases, Department of Orthopedics, Ulm University, 89081 Ulm, Germany
- Correspondence: ; Tel.: +49-(0)731-500-63280
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25
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Heggli I, Laux CJ, Mengis T, Karol A, Cornaz F, Herger N, Aradi‐Vegh B, Widmer J, Burkhard MD, Farshad‐Amacker NA, Pfammatter S, Wolski WE, Brunner F, Distler O, Farshad M, Dudli S. Modic type 2 changes are fibroinflammatory changes with complement system involvement adjacent to degenerated vertebral endplates. JOR Spine 2023; 6:e1237. [PMID: 36994463 PMCID: PMC10041382 DOI: 10.1002/jsp2.1237] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Revised: 11/04/2022] [Accepted: 12/02/2022] [Indexed: 12/25/2022] Open
Abstract
Background Vertebral endplate signal intensity changes visualized by magnetic resonance imaging termed Modic changes (MC) are highly prevalent in low back pain patients. Interconvertibility between the three MC subtypes (MC1, MC2, MC3) suggests different pathological stages. Histologically, granulation tissue, fibrosis, and bone marrow edema are signs of inflammation in MC1 and MC2. However, different inflammatory infiltrates and amount of fatty marrow suggest distinct inflammatory processes in MC2. Aims The aims of this study were to investigate (i) the degree of bony (BEP) and cartilage endplate (CEP) degeneration in MC2, (ii) to identify inflammatory MC2 pathomechanisms, and (iii) to show that these marrow changes correlate with severity of endplate degeneration. Methods Pairs of axial biopsies (n = 58) spanning the entire vertebral body including both CEPs were collected from human cadaveric vertebrae with MC2. From one biopsy, the bone marrow directly adjacent to the CEP was analyzed with mass spectrometry. Differentially expressed proteins (DEPs) between MC2 and control were identified and bioinformatic enrichment analysis was performed. The other biopsy was processed for paraffin histology and BEP/CEP degenerations were scored. Endplate scores were correlated with DEPs. Results Endplates from MC2 were significantly more degenerated. Proteomic analysis revealed an activated complement system, increased expression of extracellular matrix proteins, angiogenic, and neurogenic factors in MC2 marrow. Endplate scores correlated with upregulated complement and neurogenic proteins. Discussion The inflammatory pathomechanisms in MC2 comprises activation of the complement system. Concurrent inflammation, fibrosis, angiogenesis, and neurogenesis indicate that MC2 is a chronic inflammation. Correlation of endplate damage with complement and neurogenic proteins suggest that complement system activation and neoinnervation may be linked to endplate damage. The endplate-near marrow is the pathomechanistic site, because MC2 occur at locations with more endplate degeneration. Conclusion MC2 are fibroinflammatory changes with complement system involvement which occur adjacent to damaged endplates.
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Affiliation(s)
- Irina Heggli
- Center of Experimental Rheumatology, Balgrist Campus, University Hospital Zurich and Balgrist University Hospital, University of ZurichZurichSwitzerland
| | - Christoph J. Laux
- Department of Orthopedics, Balgrist University HospitalUniversity of ZurichZurichSwitzerland
| | - Tamara Mengis
- Center of Experimental Rheumatology, Balgrist Campus, University Hospital Zurich and Balgrist University Hospital, University of ZurichZurichSwitzerland
| | - Agnieszka Karol
- Department of Molecular Mechanisms of DiseaseUniversity of ZurichZurichSwitzerland
| | - Frédéric Cornaz
- Department of Orthopedics, Balgrist University HospitalUniversity of ZurichZurichSwitzerland
| | - Nick Herger
- Center of Experimental Rheumatology, Balgrist Campus, University Hospital Zurich and Balgrist University Hospital, University of ZurichZurichSwitzerland
| | - Borbala Aradi‐Vegh
- Center of Experimental Rheumatology, Balgrist Campus, University Hospital Zurich and Balgrist University Hospital, University of ZurichZurichSwitzerland
| | - Jonas Widmer
- Department of Orthopedics, Balgrist University HospitalUniversity of ZurichZurichSwitzerland
| | - Marco D. Burkhard
- Department of Orthopedics, Balgrist University HospitalUniversity of ZurichZurichSwitzerland
| | | | - Sibylle Pfammatter
- Functional Genomics Center Zurich, University and ETH ZurichZurichSwitzerland
| | - Witold E. Wolski
- Functional Genomics Center Zurich, University and ETH ZurichZurichSwitzerland
- Swiss Institute of BioinformaticsLausanneSwitzerland
| | - Florian Brunner
- Department of Physical Medicine and RheumatologyBalgrist University Hospital, University of ZurichZurichSwitzerland
| | - Oliver Distler
- Center of Experimental Rheumatology, Balgrist Campus, University Hospital Zurich and Balgrist University Hospital, University of ZurichZurichSwitzerland
| | - Mazda Farshad
- Department of Orthopedics, Balgrist University HospitalUniversity of ZurichZurichSwitzerland
| | - Stefan Dudli
- Center of Experimental Rheumatology, Balgrist Campus, University Hospital Zurich and Balgrist University Hospital, University of ZurichZurichSwitzerland
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26
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Macrophage Repolarization as a Therapeutic Strategy for Osteosarcoma. Int J Mol Sci 2023; 24:ijms24032858. [PMID: 36769180 PMCID: PMC9917837 DOI: 10.3390/ijms24032858] [Citation(s) in RCA: 28] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Revised: 01/31/2023] [Accepted: 01/31/2023] [Indexed: 02/05/2023] Open
Abstract
Macrophages are versatile immune cells and can adapt to both external stimuli and their surrounding environment. Macrophages are categorized into two major categories; M1 macrophages release pro-inflammatory cytokines and produce protective responses that lead to antimicrobial or antitumor activity. M2 or tumor-associated macrophages (TAM) release anti-inflammatory cytokines that support tumor growth, invasion capacity, and metastatic potential. Since macrophages can be re-polarized from an M2 to an M1 phenotype with a variety of strategies, this has emerged as an innovative anti-cancer approach. Osteosarcoma (OS) is a kind of bone cancer and consists of a complex niche, and immunotherapy is not very effective. Therefore, immediate attention to new strategies is required. We incorporated the recent studies that have used M2-M1 repolarization strategies in the aspect of treating OS cancer.
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27
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Das A, Ghosh M, Gupta PK, Rana S. Neutraligands of C5a can potentially occlude the interaction of C5a with the complement receptors C5aR1 and C5aR2. J Cell Biochem 2023; 124:266-281. [PMID: 36565188 DOI: 10.1002/jcb.30360] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2022] [Revised: 12/02/2022] [Accepted: 12/09/2022] [Indexed: 12/25/2022]
Abstract
The complement system is central to the rapid immune response witnessed in vertebrates and invertebrates, which plays a crucial role in physiology and pathophysiology. Complement activation fuels the proteolytic cascade, which produces several complement fragments that interacts with a distinct set of complement receptors. Among all the complement fragments, C5a is one of the most potent anaphylatoxins, which exerts solid pro-inflammatory responses in a myriad of tissues by binding to the complement receptors such as C5aR1 (CD88, C5aR) and C5aR2 (GPR77, C5L2), which are part of the rhodopsin subfamily of G-protein coupled receptors. In terms of signaling cascade, recruitment of C5aR1 or C5aR2 by C5a triggers the association of either G-proteins or β-arrestins, providing a protective response under normal physiological conditions and a destructive response under pathophysiological conditions. As a result, both deficiency and unregulated activation of the complement lead to clinical conditions that require therapeutic intervention. Indeed, complement therapeutics targeting either the complement fragments or the complement receptors are being actively pursued by both industry and academia. In this context, the model structural complex of C5a-C5aR1 interactions, followed by a biophysical evaluation of the model complex, has been elaborated on earlier. In addition, through the drug repurposing strategy, we have shown that small molecule drugs such as raloxifene and prednisone may act as neutraligands of C5a by effectively binding to C5a and altering its biologically active molecular conformation. Very recently, structural models illustrating the intermolecular interaction of C5a with C5aR2 have also been elaborated by our group. In the current study, we provide the biophysical validation of the C5a-C5aR2 model complex by recruiting major synthetic peptide fragments of C5aR2 against C5a. In addition, the ability of the selected neutraligands to hinder the interaction of C5a with the peptide fragments derived from both C5aR1 and C5aR2 has also been explored. Overall, the computational and experimental data provided in the current study supports the idea that small molecule drugs targeting C5a can potentially neutralize C5a's ability to interact effectively with its cognate complement receptors, which can be beneficial in modulating the destructive signaling response of C5a under pathological conditions.
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Affiliation(s)
- Aurosikha Das
- Chemical Biology Laboratory, School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Bhubaneswar, India
| | - Manaswini Ghosh
- Chemical Biology Laboratory, School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Bhubaneswar, India
| | - Pulkit Kr Gupta
- Chemical Biology Laboratory, School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Bhubaneswar, India
| | - Soumendra Rana
- Chemical Biology Laboratory, School of Basic Sciences, Indian Institute of Technology Bhubaneswar, Bhubaneswar, India
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28
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Roumani S, Jeanneau C, Giraud T, Cotten A, Laucournet M, Sohier J, Pithioux M, About I. Osteogenic Potential of a Polyethylene Glycol Hydrogel Functionalized with Poly-Lysine Dendrigrafts (DGL) for Bone Regeneration. MATERIALS (BASEL, SWITZERLAND) 2023; 16:ma16020862. [PMID: 36676600 PMCID: PMC9863473 DOI: 10.3390/ma16020862] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Revised: 12/28/2022] [Accepted: 01/12/2023] [Indexed: 05/27/2023]
Abstract
Resorbable hydrogels are widely used as scaffolds for tissue engineering. These hydrogels can be modified by grafting dendrimer-linked functionalized molecules (dendrigrafts). Our aim was to develop a tunable poly(L-lysine) dendrigrafts (DGL)/PEG-based hydrogel with an inverse porosity and to investigate its osteogenic potential. DGL/PEG hydrogels were emulsified in a surfactant-containing oil solution to form microspheres. The toxicity was evaluated on Human Vascular Endothelial Cells (HUVECs) and Bone Marrow Mesenchymal Stem Cells (hMSCs) with Live/Dead and MTT assays. The effects on HUVECs were investigated through C5 Complement expression by RT-PCR and C5a/TGF-β1 secretion by ELISA. Recruitment of hMSCs was investigated using Boyden chambers and their osteogenic differentiation was studied by measuring Alkaline Phosphatase activity (ALP) and BMP-2 secretion by ELISA. Adjusting the stirring speed during the emulsification allowed to obtain spherical microspheres with tunable diameters (10-1600 µm). The cell viability rate with the hydrogel was 95 and 100% with HUVECs and hMSCs, respectively. Incubating HUVECs with the biomaterial induced a 5-fold increase in TGF-β1 and a 3-fold increase in Complement C5a release. Furthermore, HUVEC supernatants obtained after incubation with the hydrogel induced a 2.5-fold increase in hMSC recruitment. The hydrogel induced a 3-fold increase both in hMSC ALP activity and BMP-2 secretion. Overall, the functionalized hydrogel enhanced the osteogenic potential by interacting with endothelial cells and hMSCs and represents a promising tool for bone tissue engineering.
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Affiliation(s)
- Sandra Roumani
- Aix-Marseille University, CNRS, ISM, 13009 Marseille, France
| | | | - Thomas Giraud
- Aix-Marseille University, CNRS, ISM, 13009 Marseille, France
- APHM, Hôpital Timone, Pôle Odontologie, 13005 Marseille, France
| | - Aurélie Cotten
- Aix-Marseille University, CNRS, ISM, 13009 Marseille, France
| | - Marc Laucournet
- Laboratory for Tissue Biology and Therapeutic Engineering (LBTI), UMR 5305, CNRS, Lyon University, 69367 Lyon, France
| | - Jérôme Sohier
- Laboratory for Tissue Biology and Therapeutic Engineering (LBTI), UMR 5305, CNRS, Lyon University, 69367 Lyon, France
| | - Martine Pithioux
- Aix-Marseille University, CNRS, ISM, 13009 Marseille, France
- Aix-Marseille University, APHM, CNRS, ISM, Sainte-Marguerite Hospital, Institute for Locomotion, Department of Orthopaedics and Traumatology, 13009 Marseille, France
| | - Imad About
- Aix-Marseille University, CNRS, ISM, 13009 Marseille, France
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Irfan M, Chung S. C5L2 modulates BDNF production in human dental pulp stem cells via p38α pathway. Sci Rep 2023; 13:74. [PMID: 36593314 PMCID: PMC9807628 DOI: 10.1038/s41598-022-27320-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2022] [Accepted: 12/30/2022] [Indexed: 01/03/2023] Open
Abstract
Tissue injury affects nerve fibers and triggers an immune response, leading to inflammation. The complement system gets activated during inflammatory conditions and has been reported to be involved in the regeneration process. We have demonstrated that the C5a receptor (C5aR) has crucial roles in regeneration and healing processes including nerve sprouting and hard tissue formation. Another C5a-like 2 receptor (C5AR2; C5L2) has been cloned which is still considered controversial due to limited studies. We previously established that C5L2 regulates brain-derived neurotrophic factor (BDNF) secretion in pulp fibroblasts. However, there is no study available on human dental pulp stem cells (DPSCs), especially in the inflammatory context. Stem cell therapy is an emerging technique to treat and prevent several diseases. DPSCs are a great option to be considered due to their great ability to differentiate into a variety of cells and secrete nerve regeneration factors. Here, we demonstrated that C5L2 modulates BDNF secretion in DPSCs. Our results stated that C5L2 silencing through siRNA could increase BDNF production, which could accelerate the nerve regeneration process. Moreover, stimulation with lipopolysaccharide (LPS) enhanced BDNF production in C5L2 silenced DPSCs. Finally, we quantified BDNF secretion in supernatant and cell lysates using ELISA. Our results showed enhanced BDNF production in C5L2 silenced DPSCs and hampered by the p38MAPKα inhibitor. Taken together, our data reveal that C5L2 modulates BDNF production in DPSCs via the p38MAPKα pathway.
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Affiliation(s)
- Muhammad Irfan
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, 801 S. Paulina St, Chicago, IL, 60612, USA
| | - Seung Chung
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, 801 S. Paulina St, Chicago, IL, 60612, USA.
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Gao Y, Min Q, Li X, Liu L, Lv Y, Xu W, Liu X, Wang H. Immune System Acts on Orthodontic Tooth Movement: Cellular and Molecular Mechanisms. BIOMED RESEARCH INTERNATIONAL 2022; 2022:9668610. [PMID: 36330460 PMCID: PMC9626206 DOI: 10.1155/2022/9668610] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Revised: 09/05/2022] [Accepted: 09/29/2022] [Indexed: 12/03/2022]
Abstract
Orthodontic tooth movement (OTM) is a tissue remodeling process based on orthodontic force loading. Compressed periodontal tissues have a complicated aseptic inflammatory cascade, which are considered the initial factor of alveolar bone remodeling. Since skeletal and immune systems shared a wide variety of molecules, osteoimmunology has been generally accepted as an interdisciplinary field to investigate their interactions. Unsurprisingly, OTM is considered a good mirror of osteoimmunology since it involves immune reaction and bone remolding. In fact, besides bone remodeling, OTM involves cementum resorption, soft tissue remodeling, orthodontic pain, and relapse, all correlated with immune cells and/or immunologically active substance. The aim of this paper is to review the interaction of immune system with orthodontic tooth movement, which helps gain insights into mechanisms of OTM and search novel method to short treatment period and control complications.
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Affiliation(s)
- Yajun Gao
- Department of Endodontics, Wuxi Stomatology Hospital, Wuxi, China
| | - Qingqing Min
- Department of Endodontics, Wuxi Stomatology Hospital, Wuxi, China
| | - Xingjia Li
- Department of Prosthodontics, Wuxi Stomatology Hospital, Wuxi, China
| | - Linxiang Liu
- Department of Implantology, Wuxi Stomatology Hospital, Wuxi, China
| | - Yangyang Lv
- Department of Endodontics, Wuxi Stomatology Hospital, Wuxi, China
| | - Wenjie Xu
- Department of Endodontics, Wuxi Stomatology Hospital, Wuxi, China
| | | | - Hua Wang
- Wuhu Stomatology Hospital, Wuhu, China
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Ruocco A, Sirico A, Novelli R, Iannelli S, Van Breda SV, Kyburz D, Hasler P, Aramini A, Amendola PG. The role of C5a-C5aR1 axis in bone pathophysiology: A mini-review. Front Cell Dev Biol 2022; 10:957800. [PMID: 36003145 PMCID: PMC9393612 DOI: 10.3389/fcell.2022.957800] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2022] [Accepted: 07/11/2022] [Indexed: 11/13/2022] Open
Abstract
Bone remodeling is a physiological, dynamic process that mainly depends on the functions of 2 cell types: osteoblasts and osteoclasts. Emerging evidence suggests that complement system is crucially involved in the regulation of functions of these cells, especially during inflammatory states. In this context, complement component 5a (C5a), a powerful pro-inflammatory anaphylatoxin that binds the receptor C5aR1, is known to regulate osteoclast formation and osteoblast inflammatory responses, and has thus been proposed as potential therapeutic target for the treatment of inflammatory bone diseases. In this review, we will analyze the role of C5a-C5aR1 axis in bone physiology and pathophysiology, describing its involvement in the pathogenesis of some of the most frequent inflammatory bone diseases such as rheumatoid arthritis, and also in osteoporosis and bone cancer and metastasis. Moreover, we will examine C5aR1-based pharmacological approaches that are available and have been tested so far for the treatment of these conditions. Given the growing interest of the scientific community on osteoimmunology, and the scarcity of data regarding the role of C5a-C5aR1 axis in bone pathophysiology, we will highlight the importance of this axis in mediating the interactions between skeletal and immune systems and its potential use as a therapeutic target.
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Affiliation(s)
| | | | | | | | | | - Diego Kyburz
- Departement Biomedizin, University of Basel, Basel, Switzerland
| | - Paul Hasler
- Division of Rheumatology, Kantonsspital Aarau AG, Aarau, Switzerland
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Schäfer N, Grässel S. Involvement of complement peptides C3a and C5a in osteoarthritis pathology. Peptides 2022; 154:170815. [PMID: 35598724 DOI: 10.1016/j.peptides.2022.170815] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 05/10/2022] [Accepted: 05/17/2022] [Indexed: 12/28/2022]
Abstract
Osteoarthritis (OA) affects more than 500 million people worldwide and is among the five diseases in Germany causing the highest suffering of the patients and cost for the society. The quality of life of OA patients is severely compromised, and adequate therapy is lacking owing to a knowledge gap that acts as a major barrier to finding safe and effective solutions. Chronic, low-grade inflammation plays a central role in OA pathogenesis and is associated with both OA pain and disease progression. Innate immune pathways, such as the complement- and pattern-recognition receptor pathways, are pivotal to the inflammation in OA and key components of the innate immune system implicated in OA include DAMP-TLR signaling, the complement system, carboxypeptidase B (CPB), and mononuclear cells. Anaphylatoxins C3a and C5a are small polypeptides (77 and 74 amino acids, respectively) which are released by proteolytic cleavage of the complement components C3 and C5. The alternative complement pathway seems to play a crucial role in OA pathogenesis as these complement components, mostly C3 and its activation peptide C3a, were detected at high levels in osteoarthritic cartilage, synovial membrane, and cultured chondrocytes. Targeting the complement system by using anti-complement drugs as a therapeutic option bears the risk of major side effects such as increasing the risk of infection, interfering with cell regeneration and metabolism, and suppressing the clearance of immune complexes. Despite those adverse effects, several synthetic complement peptide antagonists show promising effects in ameliorating inflammatory cell responses also in joint tissues.
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Affiliation(s)
- Nicole Schäfer
- Experimental Orthopaedics, Centre for Medical Biotechnology (ZMB), Bio Park 1, University of Regensburg, Germany
| | - Susanne Grässel
- Experimental Orthopaedics, Centre for Medical Biotechnology (ZMB), Bio Park 1, University of Regensburg, Germany; Department of Orthopaedic Surgery, University of Regensburg, Germany.
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Sehring IM, Mohammadi HF, Haffner-Luntzer M, Ignatius A, Huber-Lang M, Weidinger G. Zebrafish fin regeneration involves generic and regeneration-specific osteoblast injury responses. eLife 2022; 11:77614. [PMID: 35748539 PMCID: PMC9259016 DOI: 10.7554/elife.77614] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Accepted: 06/23/2022] [Indexed: 11/13/2022] Open
Abstract
Successful regeneration requires the coordinated execution of multiple cellular responses to injury. In amputated zebrafish fins, mature osteoblasts dedifferentiate, migrate towards the injury and form proliferative osteogenic blastema cells. We show that osteoblast migration is preceded by cell elongation and alignment along the proximodistal axis, which require actomyosin, but not microtubule turnover. Surprisingly, osteoblast dedifferentiation and migration can be uncoupled. Using pharmacological and genetic interventions, we found that NF-ĸB and retinoic acid signalling regulate dedifferentiation without affecting migration, while the complement system and actomyosin dynamics affect migration but not dedifferentiation. Furthermore, by removing bone at two locations within a fin ray, we established an injury model containing two injury sites. We found that osteoblasts dedifferentiate at and migrate towards both sites, while accumulation of osteogenic progenitor cells and regenerative bone formation only occur at the distal-facing injury. Together, these data indicate that osteoblast dedifferentiation and migration represent generic injury responses that are differentially regulated and can occur independently of each other and of regenerative growth. We conclude that successful fin bone regeneration appears to involve the coordinated execution of generic and regeneration-specific responses of osteoblasts to injury.
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Affiliation(s)
| | | | | | - Anita Ignatius
- Institute of Orthopaedic Research and Biomechanics, University Hospital Ulm, Ulm, Germany
| | - Markus Huber-Lang
- Institute of Clinical and Experimental Trauma-Immunology (ITI), University Hospital Ulm, Ulm, Germany
| | - Gilbert Weidinger
- Institute of Biochemistry and Molecular Biology, University of Ulm, Ulm, Germany
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34
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Peng R, Dong Y, Kang H, Guo Q, Zhu M, Li F. Identification of Genes with Altered Methylation in Osteoclast Differentiation and Its Roles in Osteoporosis. DNA Cell Biol 2022; 41:575-589. [PMID: 35699379 DOI: 10.1089/dna.2021.0699] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
Osteoporosis is one of the most common metabolic skeletal diseases, which affects more than 200 million people worldwide, especially elderly and postmenopausal women. One of the main processes of osteoporosis is attenuated bone formation. Abundant evidence has confirmed that overactivated osteoclasts are responsible for the attenuated bone formation. This study aims at identifying novel methylation-associated biomarkers and therapeutic targets in osteoclasts by integrally analyzing methylation profiles and gene expression data. DNA methylation profile and gene expression data were obtained from the Gene Expression Omnibus (GEO) database. Subsequently, we integrated the two sets of data to screen for differentially expressed genes with differential methylation level (DM-DEGs) between osteoclasts and CD14+ monocytes from donors. Then, Gene Ontology (GO) analysis and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were performed to uncover the enriched functions and pathways of identified DM-DEGs. In addition, by combining protein-protein interaction analysis and receiver-operator characteristic analysis, we finally identified four hub DM-DEGs. Gene Set Enrichment Analysis was utilized to validate and investigate the potential biological functions of the four hub DM-DEGs. Finally, Real-time quantitative PCR (QPCR) was performed to validate the mRNA expression level of the four identified hub DM-DEGs during osteoclast differentiation. CCRL2, CCL18, C1QB, and SELL were highly correlated with osteoclastic differentiation and osteoporosis phenotype. QPCR revealed that the expression of CCRL2, CCL18, and C1QB was increased during osteoclast differentiation, whereas the expression of SELL was decreased. The present study indicated a connection between gene expression and DNA methylation during osteoclast differentiation and that four hub DM-DEGs in osteoclastogenesis and osteoporosis pathogenesis might be potential candidates for intensive research and therapeutic targets for the treatment of osteoporosis.
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Affiliation(s)
- Renpeng Peng
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yimin Dong
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Honglei Kang
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Qian Guo
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Meipeng Zhu
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Feng Li
- Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.,Biological Engineering and Regenerative Medicine Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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35
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Garg V, Chandanala S, David-Luther M, Govind M, Prasad RR, Kumar A, Prasanna SJ. The Yin and Yang of Immunity in Stem Cell Decision Guidance in Tissue Ecologies: An Infection Independent Perspective. Front Cell Dev Biol 2022; 10:793694. [PMID: 35198558 PMCID: PMC8858808 DOI: 10.3389/fcell.2022.793694] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Accepted: 01/10/2022] [Indexed: 11/13/2022] Open
Abstract
The impact of immune system and inflammation on organ homeostasis and tissue stem cell niches in the absence of pathogen invasion has long remained a conundrum in the field of regenerative medicine. The paradoxical role of immune components in promoting tissue injury as well as resolving tissue damage has complicated therapeutic targeting of inflammation as a means to attain tissue homeostasis in degenerative disease contexts. This confound could be resolved by an integrated intricate assessment of cross-talk between inflammatory components and micro- and macro-environmental factors existing in tissues during health and disease. Prudent fate choice decisions of stem cells and their differentiated progeny are key to maintain tissue integrity and function. Stem cells have to exercise this fate choice in consultation with other tissue components. With this respect tissue immune components, danger/damage sensing molecules driving sterile inflammatory signaling cascades and barrier cells having immune-surveillance functions play pivotal roles in supervising stem cell decisions in their niches. Stem cells learn from their previous damage encounters, either endogenous or exogenous, or adapt to persistent micro-environmental changes to orchestrate their decisions. Thus understanding the communication networks between stem cells and immune system components is essential to comprehend stem cell decisions in endogenous tissue niches. Further the systemic interactions between tissue niches integrated through immune networks serve as patrolling systems to establish communication links and orchestrate micro-immune ecologies to better organismal response to injury and promote regeneration. Understanding these communication links is key to devise immune-centric regenerative therapies. Thus the present review is an integrated attempt to provide a unified purview of how inflammation and immune cells provide guidance to stem cells for tissue sculpting during development, organismal aging and tissue crisis based on the current knowledge in the field.
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Irfan M, Kim JH, Druzinsky RE, Ravindran S, Chung S. Complement C5aR/LPS-induced BDNF and NGF modulation in human dental pulp stem cells. Sci Rep 2022; 12:2042. [PMID: 35132159 PMCID: PMC8821590 DOI: 10.1038/s41598-022-06110-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Accepted: 01/24/2022] [Indexed: 12/12/2022] Open
Abstract
Stem cells with the ability to differentiate into a variety of cells and secrete nerve regeneration factors have become an emerging option in nerve regeneration. Dental pulp stem cells (DPSCs) appear to be a good candidate for nerve regeneration given their accessibility, neural crest origin, and neural repair qualities. We have recently demonstrated that the complement C5a system, which is an important mediator of inflammation and tissue regeneration, is activated by lipoteichoic acid-treated pulp fibroblasts, and governs the production of brain-derived nerve growth factor (BDNF). This BDNF secretion promotes neurite outgrowth towards the injury site. Here, we extend our observation to DPSCs and compare their neurogenic ability to bone marrow-derived mesenchymal stem cells (BM-MSCs) under inflammatory stimulation. Our ELISA and immunostaining data demonstrate that blocking the C5a receptor (C5aR) reduced BDNF production in DPSCs, while treatment with C5aR agonist increased the BDNF expression, which suggests that C5aR has a positive regulatory role in the BDNF modulation of DPSCs. Inflammation induced by lipopolysaccharide (LPS) treatment potentiated this effect and is C5aR dependent. Most important, DPSCs produced significantly higher levels of C5aR-mediated BDNF compared to BM-MSCs. Taken together, our data reveal novel roles for C5aR and inflammation in modulation of BDNF and NGF in DPSCs.
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Affiliation(s)
- Muhammad Irfan
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, 801 S. Paulina St, Chicago, IL, 60612, USA
| | - Ji Hyun Kim
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, 801 S. Paulina St, Chicago, IL, 60612, USA
| | - Robert E Druzinsky
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, 801 S. Paulina St, Chicago, IL, 60612, USA
| | - Sriram Ravindran
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, 801 S. Paulina St, Chicago, IL, 60612, USA
| | - Seung Chung
- Department of Oral Biology, College of Dentistry, University of Illinois Chicago, 801 S. Paulina St, Chicago, IL, 60612, USA.
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The role of complement C5a receptor in DPSC odontoblastic differentiation and in vivo reparative dentin formation. Int J Oral Sci 2022; 14:7. [PMID: 35087028 PMCID: PMC8795457 DOI: 10.1038/s41368-022-00158-4] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Revised: 12/18/2021] [Accepted: 12/28/2021] [Indexed: 12/20/2022] Open
Abstract
Therapeutic dentin regeneration remains difficult to achieve, and a majority of the attention has been given to anabolic strategies to promote dentinogenesis directly, whereas, the available literature is insufficient to understand the role of inflammation and inflammatory complement system on dentinogenesis. The aim of this study is to determine the role of complement C5a receptor (C5aR) in regulating dental pulp stem cells (DPSCs) differentiation and in vivo dentin regeneration. Human DPSCs were subjected to odontogenic differentiation in osteogenic media treated with the C5aR agonist and C5aR antagonist. In vivo dentin formation was evaluated using the dentin injury/pulp-capping model of the C5a-deficient and wild-type mice. In vitro results demonstrate that C5aR inhibition caused a substantial reduction in odontogenic DPSCs differentiation markers such as DMP-1 and DSPP, while the C5aR activation increased these key odontogenic genes compared to control. A reparative dentin formation using the C5a-deficient mice shows that dentin regeneration is significantly reduced in the C5a-deficient mice. These data suggest a positive role of C5aR in the odontogenic DPSCs differentiation and tertiary/reparative dentin formation. This study addresses a novel regulatory pathway and a therapeutic approach for improving the efficiency of dentin regeneration in affected teeth.
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Activation of C3 and C5 May Be Involved in the Inflammatory Progression of PCM and GM. Inflammation 2022; 45:739-752. [PMID: 34997873 DOI: 10.1007/s10753-021-01580-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 10/05/2021] [Accepted: 10/06/2021] [Indexed: 11/05/2022]
Abstract
Plasma cell mastitis (PCM) and granulomatous mastitis (GM) are the most common inflammatory diseases constituting nonbacterial mastitis (NBM). However, the pathogenesis of NBM remains unclear. In this study, risk factors for NBM were assessed, as well as the pathological features of PCM and GM. The levels of C3/C3a-C3aR and C5/C5a-C5aR1 of tissues were detected by IHC and WB. Exosomes were isolated from serum and identified by transmission electron microscopy. Then, C3 and C5 levels were detected in peripheral blood, and exosomes were assessed by flow cytometry and immunoelectron microscopy. Obesity and prolonged lactation were risk factors for NBM. The infiltration of plasma cells and lymphocytes around the dilated catheter in PCM and the formation of granulomatous structures in GM were the respective pathological features. C3/C3a-C3aR and C5/C5a-C5aR1 levels were elevated in PCM and GM tissue samples. There were no differences in peripheral blood levels of C3 and C5, while C3a and C5a were highly expressed in exosomes. These results suggest that the complement family is activated in PCM and GM, exosomes enrich C3a and C5a, and mediate the spread of inflammation. These findings provide new insights into the molecular mechanisms of PCM and GM and identify therapeutic targets.
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Bülow JM, Renz N, Haffner-Luntzer M, Fischer V, Schoppa A, Tuckermann J, Köhl J, Huber-Lang M, Ignatius A. Complement receptor C5aR1 on osteoblasts regulates osteoclastogenesis in experimental postmenopausal osteoporosis. Front Endocrinol (Lausanne) 2022; 13:1016057. [PMID: 36246887 PMCID: PMC9561253 DOI: 10.3389/fendo.2022.1016057] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/10/2022] [Accepted: 09/14/2022] [Indexed: 11/25/2022] Open
Abstract
In recent years, evidence has accumulated that the complement system, an integral part of innate immunity, may be involved in the regulation of bone homeostasis as well as inflammatory bone loss, for example, in rheumatoid arthritis and periodontitis. Complement may also contribute to osteoporosis development, but investigation of the mechanism is limited. Using mice with a conditional deletion of the complement anaphylatoxin receptor C5aR1, we here demonstrated that C5aR1 in osteoblasts (C5aR1 Runx2-Cre mice) or osteoclasts (C5aR1 LysM-Cre mice) did not affect physiological bone turnover or age-related bone loss in either sex, as confirmed by micro-computed tomography, histomorphometry, and biomechanical analyses of the bone and by the measurement of bone turnover markers in the blood serum. When female mice were subjected to ovariectomy (OVX), a common model for postmenopausal osteoporosis, significant bone loss was induced in C5aR1 fl/fl and C5aR1 LysM-Cre mice, as demonstrated by a significantly reduced bone volume fraction, trabecular number and thickness as well as an increased trabecular separation in the trabecular bone compartment. Confirming this, the osteoclast number and the receptor activator of nuclear factor k-B (RANK) ligand (RANKL) serum level were significantly elevated in these mouse lines. By contrast, C5aR1 Runx2-Cre mice were protected from bone loss after OVX and the serum RANKL concentration was not increased after OVX. These data suggested that bone cell-specific C5aR1 may be redundant in bone homeostasis regulation under physiological conditions. However, C5aR1 on osteoblasts was crucial for the induction of bone resorption under osteoporotic conditions by stimulating RANKL release, whereas C5aR1 on osteoclasts did not regulate OVX-induced bone loss. Therefore, our results implicate C5aR1 on osteoblasts as a potential target for treating postmenopausal osteoporosis.
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Affiliation(s)
- Jasmin Maria Bülow
- Institute of Orthopedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany
| | - Nikolai Renz
- Institute of Orthopedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany
| | - Melanie Haffner-Luntzer
- Institute of Orthopedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany
| | - Verena Fischer
- Institute of Orthopedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany
| | - Astrid Schoppa
- Institute of Orthopedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany
| | - Jan Tuckermann
- Institute of Comparative Molecular Endocrinology, University of Ulm, Ulm, Germany
| | - Jörg Köhl
- Institute for Systemic Inflammation Research, University of Lübeck, Lübeck, Germany
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, OH, United States
| | - Markus Huber-Lang
- Institute of Clinical and Experimental Trauma-Immunology, Ulm University Medical Center, Ulm, Germany
| | - Anita Ignatius
- Institute of Orthopedic Research and Biomechanics, Ulm University Medical Center, Ulm, Germany
- *Correspondence: Anita Ignatius,
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Mistegaard CE, Proft F, Department of Biomedicine, Aarhus University, Aarhus, Denmark, Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark, Department of Gastroenterology, Infectiology and Rheumatology (including Nutrition Medicine), Charité – Universitätsmedizin Berlin, Berlin, Germany, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany. The Complement System in Spondyloarthritis: What Do We Know? Rheumatology (Oxford) 2022. [DOI: 10.17925/rmd.2022.1.2.50] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Spondyloarthritis (SpA) encompasses a group of rheumatologic diseases, including axial spondyloarthritis (axSpA), psoriatic arthritis, arthritis with associated inflammatory bowel disease (i.e. Crohn’s disease and ulcerative colitis), reactive arthritis and undifferentiated SpA, which all share certain clinical, biological and genetic features. However, the pathogenesis remains largely unexplained. Recent evidence suggests an autoinflammatory component of the disease. The complement system is a cornerstone of the innate immune system. This review aims to evaluate the current knowledge of the complement system in SpA. Animal models have shown that complement activation is associated with axSpA. Complement proteins L-ficolin and H-ficolin levels are elevated in patients with axSpA, and complement factor C3 levels decrease after the initiation of tumour necrosis factor-inhibitor therapy. Associations with disease activity are inconsistent, as one study found that the serum levels of complement factors C3 and C4 did not differ in patients with different Bath Ankylosing Spondylitis Disease Activity Index scores but, in another study, were associated with baseline Ankylosing Spondylitis Disease Activity Score with C-reactive protein and Bath Ankylosing Spondylitis Disease Activity Index improvement after treatment with a tumour necrosis factor inhibitor. Future studies should focus on the complement system in various SpA entities, involvement in pathogenesis and disease progression under clinically relevant conditions.
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Mesenchymal stem cell therapy attenuates complement C3 deposition and improves the delicate equilibrium between angiogenic and anti-angiogenic factors in abortion-prone mice. Mol Immunol 2021; 141:246-256. [PMID: 34875452 DOI: 10.1016/j.molimm.2021.11.010] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 10/15/2021] [Accepted: 11/10/2021] [Indexed: 12/12/2022]
Abstract
Immunological disorders are one of the main causes of recurrent spontaneous abortions (RSA). A rapidly expanding body of evidence indicates that excessive activation of the complement system is critically involved in the development of miscarriages. In the CBA/J × DBA/2 murine model of recurrent miscarriage, exaggerated and unrestrained complement activation is reported to be the underlying cause of angiogenic factor imbalance and persistent inflammation. We have previously shown that mesenchymal stem cell (MSC) therapy can significantly reduce the abortion rate in abortion-prone mice through regulating the feto-maternal immune response. In the present study, we hypothesized that MSCs might improve the balance of angiogenic factors at the feto-maternal unit of CBA/J × DBA/2 mice by restraining complement activation and deposition. To explore this hypothesis, autologous adipose tissue-derived mesenchymal stem cells (AD-MSCs) were administered intra-peritoneally to abortion-prone mice on the 4.5th day of gestation. Control mice received PBS as vehicle. On day 13.5 of pregnancy, deposition of the complement component C3 and expression levels of Crry, CFD (adipsin), VEGF, PlGF and FLT-1 were measured at the feto-maternal interface by immunohistochemistry and real-time PCR, respectively. Decidual cells were also cultured in RPMI 1640 medium for 48 h and VEGF and sFLT-1 protein levels were quantified in supernatants using enzyme-linked immunosorbent assay (ELISA). Our results indicated that MSC therapy significantly reduced C3 deposition and adipsin transcription in the fetal-maternal interface of abortion-prone mice. Furthermore, administration of MSCs robustly upregulated the mRNA expression levels of Crry, VEGF, PlGF and FLT-1 in the placenta and decidua of CBA/J × DBA/2 mice. Consistently, the in vitro results demonstrated that decidual cells obtained from MSC-treated dams produced increased concentrations of VEGF in culture supernatants, with concomitant decreased levels of sFLT-1 protein. Here, we show for the first time that adoptive transfer of MSCs rectifies the disturbed balance of angiogenic factors observed at the feto-maternal unit of CBA/J × DBA/2 mice, in part at least, through inhibiting excessive complement activation and promoting the production of angiogenic factors. Collectively, these alterations seem to play a pivotal role in reducing the abortion rate and improving the intrauterine condition for the benefit of the fetus.
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Gorman DM, Li XX, Lee JD, Fung JN, Cui CS, Lee HS, Rolfe BE, Woodruff TM, Clark RJ. Development of Potent and Selective Agonists for Complement C5a Receptor 1 with In Vivo Activity. J Med Chem 2021; 64:16598-16608. [PMID: 34762432 DOI: 10.1021/acs.jmedchem.1c01174] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The anaphylatoxin C5a is a complement peptide associated with immune-related disorders. C5a binds with equal potency to two GPCRs, C5aR1 and C5aR2. Multiple C5a peptide agonists have been developed to interrogate the C5a receptor function but none show selectivity for C5aR1. To address these limitations, we developed potent and stable peptide C5aR1 agonists that display no C5aR2 activity and over 1000-fold selectivity for C5aR1 over C3aR. This includes BM213, which induces C5aR1-mediated calcium mobilization and pERK1/2 signaling but not β-arrestin recruitment, and BM221, which exhibits no signaling bias. Both ligands are functionally similar to C5a in human macrophage cytokine release assays and in a murine in vivo neutrophil mobilization assay. BM213 showed antitumor activity in a mouse model of mammary carcinoma. We anticipate that these C5aR1-selective agonists will be useful research tools to investigate C5aR1 function.
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Affiliation(s)
- Declan M Gorman
- School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Xaria X Li
- School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - John D Lee
- School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Jenny N Fung
- School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Cedric S Cui
- School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Han Siean Lee
- School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Barbara E Rolfe
- Australian Institute for Bioengineering and Nanotechnology, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Trent M Woodruff
- School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia.,Queensland Brain Institute, The University of Queensland, Brisbane, Queensland 4072, Australia
| | - Richard J Clark
- School of Biomedical Sciences, The University of Queensland, Brisbane, Queensland 4072, Australia
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Reinehr S, Doerner JD, Mueller-Buehl AM, Koch D, Fuchshofer R, Dick HB, Joachim SC. Cytokine and Complement Response in the Glaucomatous βB1-CTGF Mouse Model. Front Cell Neurosci 2021; 15:718087. [PMID: 34867198 PMCID: PMC8637215 DOI: 10.3389/fncel.2021.718087] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Accepted: 10/22/2021] [Indexed: 11/13/2022] Open
Abstract
Glaucoma is a complex neurodegenerative disease leading to a loss of retinal ganglion cells (RGCs) and optic nerve axons. An activation of the complement system seems to contribute to cell loss in this disease. Hence, we investigated a possible initiation of the complement system and the cytokine response in the βB1-CTGF glaucoma model. In these mice, intraocular pressure is elevated, which is the main glaucoma risk factor in patients, and RGC loss occurs at 15 weeks of age. Therefore, quantitative real-time PCR and immunohistological experiments were performed in 5-, 10-, and 15-week-old βB1-CTGF animals and their corresponding wildtypes (WT) to analyze the expression of several complement system factors. We could show that mRNA levels of the terminal complement pathway components C3 and C5 (Hc) were upregulated at 10 weeks. In accordance, more C3+ and membrane attack complex+ cells were observed in transgenic retinae. Further, the C5a receptor anaphylatoxin receptor (C5ar) and the complement component C5a receptor 1 (C5ar1; CD88) mRNA levels were upregulated in 10- and 15-week-old βB1-CTGF mice. Interestingly, all three activation routes of the complement system were elevated in βB1-CTGF mice at some age. Especially C1q, as a marker of the classical pathway, was significantly increased at all investigated ages. Furthermore, mRNA expression levels of interferon-γ (Infg) were upregulated at 5 weeks, while Cxcl1 and Cxcl2 mRNA levels were upregulated at 10 and 15 weeks. The mRNA levels of the chemokines Cxcl10 were increased at all ages in βB1-CTGF mice. These results lead to the assumption that in these transgenic mice, a complement activation mainly through the classical pathway as well as a cytokine response plays a major role in cell death.
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Affiliation(s)
- Sabrina Reinehr
- Experimental Eye Research Institute, University Eye Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Johanna D. Doerner
- Experimental Eye Research Institute, University Eye Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Ana M. Mueller-Buehl
- Experimental Eye Research Institute, University Eye Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Dennis Koch
- Experimental Eye Research Institute, University Eye Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Rudolf Fuchshofer
- Institute of Human Anatomy and Embryology, University Regensburg, Regensburg, Germany
| | - H. Burkhard Dick
- Experimental Eye Research Institute, University Eye Hospital, Ruhr-University Bochum, Bochum, Germany
| | - Stephanie C. Joachim
- Experimental Eye Research Institute, University Eye Hospital, Ruhr-University Bochum, Bochum, Germany
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Rimal R, Desai P, Marquez AB, Sieg K, Marquardt Y, Singh S. 3-D vascularized breast cancer model to study the role of osteoblast in formation of a pre-metastatic niche. Sci Rep 2021; 11:21966. [PMID: 34754042 PMCID: PMC8578551 DOI: 10.1038/s41598-021-01513-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 10/25/2021] [Indexed: 02/06/2023] Open
Abstract
Breast cancer cells (BCCs) preferentially metastasize to bone. It is known that BCCs remotely primes the distant bone site prior to metastasis. However, the reciprocal influence of bone cells on the primary tumor is relatively overlooked. Here, to study the bone-tumor paracrine influence, a tri-cellular 3-D vascularized breast cancer tissue (VBCTs) model is engineered which comprised MDA-MB231, a triple-negative breast cancer cells (TNBC), fibroblasts, and endothelial cells. This is indirectly co-cultured with osteoblasts (OBs), thereby constituting a complex quad-cellular tumor progression model. VBCTs alone and in conjunction with OBs led to abnormal vasculature and reduced vessel density but enhanced VEGF production. A total of 1476 significantly upregulated and 775 downregulated genes are identified in the VBCTs exposed to OBs. HSP90N, CYCS, RPS27A, and EGFR are recognized as upregulated hub-genes. Kaplan Meier plot shows HSP90N to have a significant outcome in TNBC patient survivability. Furthermore, compared to cancer tissues without vessels, gene analysis recognized 1278 significantly upregulated and 566 downregulated genes in VBCTs. DKK1, CXCL13, C3 protein and BMP4 are identified to be downregulated hub genes in VBCTs. Together, a multi-cellular breast cancer model and culture protocols are established to study pre-metastatic events in the presence of OBs.
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Affiliation(s)
- Rahul Rimal
- DWI-Leibniz Institute for Interactive Materials, Forkenbeckstrasse 50, 52074, Aachen, Germany
| | - Prachi Desai
- DWI-Leibniz Institute for Interactive Materials, Forkenbeckstrasse 50, 52074, Aachen, Germany
| | - Andrea Bonnin Marquez
- DWI-Leibniz Institute for Interactive Materials, Forkenbeckstrasse 50, 52074, Aachen, Germany
| | - Karina Sieg
- DWI-Leibniz Institute for Interactive Materials, Forkenbeckstrasse 50, 52074, Aachen, Germany
| | - Yvonne Marquardt
- Department of Dermatology and Allergology, University Hospital, RWTH Aachen University, 52074, Aachen, Germany
| | - Smriti Singh
- DWI-Leibniz Institute for Interactive Materials, Forkenbeckstrasse 50, 52074, Aachen, Germany.
- Max Planck Institute for Medical Research, Jahnstrasse 29, 69120, Heidelberg, Germany.
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Saxena Y, Routh S, Mukhopadhaya A. Immunoporosis: Role of Innate Immune Cells in Osteoporosis. Front Immunol 2021; 12:687037. [PMID: 34421899 PMCID: PMC8374941 DOI: 10.3389/fimmu.2021.687037] [Citation(s) in RCA: 114] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2021] [Accepted: 07/22/2021] [Indexed: 12/11/2022] Open
Abstract
Osteoporosis or porous bone disorder is the result of an imbalance in an otherwise highly balanced physiological process known as 'bone remodeling'. The immune system is intricately involved in bone physiology as well as pathologies. Inflammatory diseases are often correlated with osteoporosis. Inflammatory mediators such as reactive oxygen species (ROS), and pro-inflammatory cytokines and chemokines directly or indirectly act on the bone cells and play a role in the pathogenesis of osteoporosis. Recently, Srivastava et al. (Srivastava RK, Dar HY, Mishra PK. Immunoporosis: Immunology of Osteoporosis-Role of T Cells. Frontiers in immunology. 2018;9:657) have coined the term "immunoporosis" to emphasize the role of immune cells in the pathology of osteoporosis. Accumulated pieces of evidence suggest both innate and adaptive immune cells contribute to osteoporosis. However, innate cells are the major effectors of inflammation. They sense various triggers to inflammation such as pathogen-associated molecular patterns (PAMPs), damage-associated molecular patterns (DAMPs), cellular stress, etc., thus producing pro-inflammatory mediators that play a critical role in the pathogenesis of osteoporosis. In this review, we have discussed the role of the innate immune cells in great detail and divided these cells into different sections in a systemic manner. In the beginning, we talked about cells of the myeloid lineage, including macrophages, monocytes, and dendritic cells. This group of cells explicitly influences the skeletal system by the action of production of pro-inflammatory cytokines and can transdifferentiate into osteoclast. Other cells of the myeloid lineage, such as neutrophils, eosinophils, and mast cells, largely impact osteoporosis via the production of pro-inflammatory cytokines. Further, we talked about the cells of the lymphoid lineage, including natural killer cells and innate lymphoid cells, which share innate-like properties and play a role in osteoporosis. In addition to various innate immune cells, we also discussed the impact of classical pro-inflammatory cytokines on osteoporosis. We also highlighted the studies regarding the impact of physiological and metabolic changes in the body, which results in chronic inflammatory conditions such as ageing, ultimately triggering osteoporosis.
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Affiliation(s)
- Yogesh Saxena
- Department of Biological Sciences, Indian Institute of Science Education and Research Mohali, Mohali, India
| | - Sanjeev Routh
- Department of Biological Sciences, Indian Institute of Science Education and Research Mohali, Mohali, India
| | - Arunika Mukhopadhaya
- Department of Biological Sciences, Indian Institute of Science Education and Research Mohali, Mohali, India
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Khella CM, Horvath JM, Asgarian R, Rolauffs B, Hart ML. Anti-Inflammatory Therapeutic Approaches to Prevent or Delay Post-Traumatic Osteoarthritis (PTOA) of the Knee Joint with a Focus on Sustained Delivery Approaches. Int J Mol Sci 2021; 22:8005. [PMID: 34360771 PMCID: PMC8347094 DOI: 10.3390/ijms22158005] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 07/20/2021] [Accepted: 07/22/2021] [Indexed: 12/11/2022] Open
Abstract
Inflammation plays a central role in the pathogenesis of knee PTOA after knee trauma. While a comprehensive therapy capable of preventing or delaying post-traumatic osteoarthritis (PTOA) progression after knee joint injury does not yet clinically exist, current literature suggests that certain aspects of early post-traumatic pathology of the knee joint may be prevented or delayed by anti-inflammatory therapeutic interventions. We discuss multifaceted therapeutic approaches that may be capable of effectively reducing the continuous cycle of inflammation and concomitant processes that lead to cartilage degradation as well as those that can simultaneously promote intrinsic repair processes. Within this context, we focus on early disease prevention, the optimal timeframe of treatment and possible long-lasting sustained delivery local modes of treatments that could prevent knee joint-associated PTOA symptoms. Specifically, we identify anti-inflammatory candidates that are not only anti-inflammatory but also anti-degenerative, anti-apoptotic and pro-regenerative.
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Affiliation(s)
| | | | | | | | - Melanie L. Hart
- G.E.R.N. Center for Tissue Replacement, Regeneration & Neogenesis, Department of Orthopedics and Trauma Surgery, Faculty of Medicine, Medical Center—Albert-Ludwigs—University of Freiburg, 79085 Freiburg im Breisgau, Germany; (C.M.K.); (J.M.H.); (R.A.); (B.R.)
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Jiang F, Liu H, Peng F, Liu Z, Ding K, Song J, Li L, Chen J, Shao Q, Yan S, De Veirman K, Vanderkerken K, Fu R. Complement C3a activates osteoclasts by regulating the PI3K/PDK1/SGK3 pathway in patients with multiple myeloma. Cancer Biol Med 2021; 18:j.issn.2095-3941.2020.0430. [PMID: 33960177 PMCID: PMC8330530 DOI: 10.20892/j.issn.2095-3941.2020.0430] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 11/27/2020] [Indexed: 11/17/2022] Open
Abstract
OBJECTIVE Myeloma bone disease (MBD) is the most common complication of multiple myeloma (MM). Our previous study showed that the serum levels of C3/C4 in MM patients were significantly positively correlated with the severity of bone disease. However, the mechanism of C3a/C4a in osteoclasts MM patients remains unclear. METHODS The formation and function of osteoclasts were analyzed after adding C3a/C4a in vitro. RNA-seq analysis was used to screen the potential pathways affecting osteoclasts, and the results were verified by Western blot, qRT-PCR, and pathway inhibitors. RESULTS The osteoclast area per view induced by 1 μg/mL (mean ± SD: 50.828 ± 12.984%) and 10 μg/mL (53.663 ± 12.685%) of C3a was significantly increased compared to the control group (0 μg/mL) (34.635 ± 8.916%) (P < 0.001 and P < 0.001, respectively). The relative mRNA expressions of genes, OSCAR/TRAP/RANKL/cathepsin K, induced by 1 μg/mL (median: 5.041, 3.726, 1.638, and 4.752, respectively) and 10 μg/mL (median: 5.140, 3.702, 2.250, and 5.172, respectively) of C3a was significantly increased compared to the control group (median: 3.137, 2.004, 0.573, and 2.257, respectively) (1 μg/mL P = 0.001, P = 0.003, P < 0.001, and P = 0.008, respectively; 10 μg/mL: P < 0.001, P = 0.019, P < 0.001, and P = 0.002, respectively). The absorption areas of the osteoclast resorption pits per view induced by 1 μg/mL (mean ± SD: 51.464 ± 11.983%) and 10 μg/mL (50.219 ± 12.067%) of C3a was also significantly increased (33.845 ± 8.331%) (P < 0.001 and P < 0.001, respectively) compared to the control. There was no difference between the C4a and control groups. RNA-seq analysis showed that C3a promoted the proliferation of osteoclasts using the phosphoinositide 3-kinase (PI3K) signaling pathway. The relative expressions of PIK3CA/phosphoinositide dependent kinase-1 (PDK1)/serum and glucocorticoid inducible protein kinases (SGK3) genes and PI3K/PDK1/p-SGK3 protein in the C3a group were significantly higher than in the control group. The activation role of C3a in osteoclasts of MM patients was reduced by the SGK inhibitor (EMD638683). CONCLUSIONS C3a activated osteoclasts by regulating the PI3K/PDK1/SGK3 pathways in MM patients, which was reduced using a SGK inhibitor. Overall, our results identified potential therapeutic targets and strategies for MBD patients.
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Affiliation(s)
- Fengjuan Jiang
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Hui Liu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Fengping Peng
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Zhaoyun Liu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Kai Ding
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Jia Song
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Lijuan Li
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Jin Chen
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Qing Shao
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Siyang Yan
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, China
| | - Kim De Veirman
- Department of Hematology and Immunology-Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels 1090, Belgium
| | - Karin Vanderkerken
- Department of Hematology and Immunology-Myeloma Center Brussels, Vrije Universiteit Brussel, Brussels 1090, Belgium
| | - Rong Fu
- Department of Hematology, Tianjin Medical University General Hospital, Tianjin 300052, China
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Zhu L, Zhang J, Wang J, Lv X, Pu D, Wang Y, Men Q, He L. Uncoupled bone remodeling is characteristic of bone damage in premenopausal women with new-onset systemic lupus erythematosus. Lupus 2021; 30:1116-1123. [PMID: 33832361 DOI: 10.1177/09612033211005067] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVE To investigate the mechanism underlying systemic lupus erythematosus (SLE)-related bone loss by evaluating the bone mineral density (BMD) and bone turnover markers (BTMs) in premenopausal patients with new-onset SLE without any treatment. METHODS BMD and BTMs of 106 premenopausal patients with new-onset SLE and 64 gender-, age- and body mass index (BMI)-matched healthy controls were analyzed. BMD was determined using dual energy X-ray absorptiometry (DXA). Serum BTMs were measured. RESULTS Hip and lumbar spine BMD in premenopausal patients with new-onset SLE was significantly decreased compared with healthy controls. Higher rate of osteoporosis was observed in new-onset SLE patients (25% vs. 1%). Moreover, uncoupled bone remodeling evidenced by an increase in bone resorption marker β-CTX (685.9 ± 709.6 pg/mL vs. 395.4 ± 326.0 pg/mL, P < 0.05) and decrease in bone formation markers PINP (37.4 ± 33.0 ng/mL vs. 46.1 ± 20.9 ng/mL, P < 0.05) and OC (11.4 ± 9.8 ng/mL vs. 18.2 ± 8.6 ng/mL, P < 0.05) was observed in premenopausal patients with new-onset SLE compared with healthy controls. Univariate correlation analyses showed negative correlations between OC and SLE Disease Activity Index (SLEDAI), and positive correlations between β-CTX and SLEDAI. SLE patients positive for dsDNA, nucleosome showed lower OC and higher β-CTX. CONCLUSION Premenopausal patients with new-onset SLE had decreased BMD and abnormal bone metabolism with increased β-CTX and decreased OC and P1NP levels, indicating uncoupled bone remodeling in new-onset SLE patients. Disease activity and abnormal immunity, especially the amount of antibodies in SLE patients, were strongly associated with abnormality of bone metabolism.
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Affiliation(s)
- Li Zhu
- Department of Rheumatology and Immunology, First Affiliated Hospital of Xi'an, JiaoTong University, Xi'an, China
| | - Jing Zhang
- Department of Rheumatology and Immunology, First Affiliated Hospital of Xi'an, JiaoTong University, Xi'an, China
| | - Jing Wang
- Department of Rheumatology and Immunology, First Affiliated Hospital of Xi'an, JiaoTong University, Xi'an, China
| | - Xiaohong Lv
- Department of Rheumatology and Immunology, First Affiliated Hospital of Xi'an, JiaoTong University, Xi'an, China
| | - Dan Pu
- Department of Rheumatology and Immunology, First Affiliated Hospital of Xi'an, JiaoTong University, Xi'an, China
| | - Yanhua Wang
- Department of Rheumatology and Immunology, First Affiliated Hospital of Xi'an, JiaoTong University, Xi'an, China
| | - Qian Men
- Department of Rheumatology and Immunology, First Affiliated Hospital of Xi'an, JiaoTong University, Xi'an, China
| | - Lan He
- Department of Rheumatology and Immunology, First Affiliated Hospital of Xi'an, JiaoTong University, Xi'an, China
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Luntzer K, Lackner I, Weber B, Mödinger Y, Ignatius A, Gebhard F, Mihaljevic SY, Haffner-Luntzer M, Kalbitz M. Increased Presence of Complement Factors and Mast Cells in Alveolar Bone and Tooth Resorption. Int J Mol Sci 2021; 22:ijms22052759. [PMID: 33803323 PMCID: PMC7967164 DOI: 10.3390/ijms22052759] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2021] [Revised: 02/24/2021] [Accepted: 03/03/2021] [Indexed: 02/07/2023] Open
Abstract
Periodontitis is the inflammatory destruction of the tooth-surrounding and -supporting tissue, resulting at worst in tooth loss. Another locally aggressive disease of the oral cavity is tooth resorption (TR). This is associated with the destruction of the dental mineralized tissue. However, the underlying pathomechanisms remain unknown. The complement system, as well as mast cells (MCs), are known to be involved in osteoclastogenesis and bone loss. The complement factors C3 and C5 were previously identified as key players in periodontal disease. Therefore, we hypothesize that complement factors and MCs might play a role in alveolar bone and tooth resorption. To investigate this, we used the cat as a model because of the naturally occurring high prevalence of both these disorders in this species. Teeth, gingiva samples and serum were collected from domestic cats, which had an appointment for dental treatment under anesthesia, as well as from healthy cats. Histological analyses, immunohistochemical staining and the CH-50 and AH-50 assays revealed increased numbers of osteoclasts and MCs, as well as complement activity in cats with TR. Calcifications score in the gingiva was highest in animals that suffer from TR. This indicates that MCs and the complement system are involved in the destruction of the mineralized tissue in this condition.
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Affiliation(s)
- Kathrin Luntzer
- Center for Trauma Research Ulm (ZTF), University of Ulm, 89081 Ulm, Germany; (K.L.); (I.L.); (B.W.); (Y.M.); (A.I.); (F.G.); (M.H.-L.)
- Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, University Medical Center, 89081 Ulm, Germany
- Small Animal Clinic Ravensburg Evidensia GmbH, Eywiesenstraße 4, 88212 Ravensburg, Germany
| | - Ina Lackner
- Center for Trauma Research Ulm (ZTF), University of Ulm, 89081 Ulm, Germany; (K.L.); (I.L.); (B.W.); (Y.M.); (A.I.); (F.G.); (M.H.-L.)
- Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, University Medical Center, 89081 Ulm, Germany
| | - Birte Weber
- Center for Trauma Research Ulm (ZTF), University of Ulm, 89081 Ulm, Germany; (K.L.); (I.L.); (B.W.); (Y.M.); (A.I.); (F.G.); (M.H.-L.)
- Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, University Medical Center, 89081 Ulm, Germany
| | - Yvonne Mödinger
- Center for Trauma Research Ulm (ZTF), University of Ulm, 89081 Ulm, Germany; (K.L.); (I.L.); (B.W.); (Y.M.); (A.I.); (F.G.); (M.H.-L.)
- Institute of Orthopedic Research and Biomechanics, University of Ulm, 89081 Ulm, Germany
| | - Anita Ignatius
- Center for Trauma Research Ulm (ZTF), University of Ulm, 89081 Ulm, Germany; (K.L.); (I.L.); (B.W.); (Y.M.); (A.I.); (F.G.); (M.H.-L.)
- Institute of Orthopedic Research and Biomechanics, University of Ulm, 89081 Ulm, Germany
| | - Florian Gebhard
- Center for Trauma Research Ulm (ZTF), University of Ulm, 89081 Ulm, Germany; (K.L.); (I.L.); (B.W.); (Y.M.); (A.I.); (F.G.); (M.H.-L.)
- Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, University Medical Center, 89081 Ulm, Germany
| | | | - Melanie Haffner-Luntzer
- Center for Trauma Research Ulm (ZTF), University of Ulm, 89081 Ulm, Germany; (K.L.); (I.L.); (B.W.); (Y.M.); (A.I.); (F.G.); (M.H.-L.)
- Institute of Orthopedic Research and Biomechanics, University of Ulm, 89081 Ulm, Germany
| | - Miriam Kalbitz
- Center for Trauma Research Ulm (ZTF), University of Ulm, 89081 Ulm, Germany; (K.L.); (I.L.); (B.W.); (Y.M.); (A.I.); (F.G.); (M.H.-L.)
- Department of Traumatology, Hand-, Plastic-, and Reconstructive Surgery, University Medical Center, 89081 Ulm, Germany
- Correspondence:
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Khella CM, Asgarian R, Horvath JM, Rolauffs B, Hart ML. An Evidence-Based Systematic Review of Human Knee Post-Traumatic Osteoarthritis (PTOA): Timeline of Clinical Presentation and Disease Markers, Comparison of Knee Joint PTOA Models and Early Disease Implications. Int J Mol Sci 2021; 22:1996. [PMID: 33671471 PMCID: PMC7922905 DOI: 10.3390/ijms22041996] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 02/05/2021] [Accepted: 02/08/2021] [Indexed: 12/15/2022] Open
Abstract
Understanding the causality of the post-traumatic osteoarthritis (PTOA) disease process of the knee joint is important for diagnosing early disease and developing new and effective preventions or treatments. The aim of this review was to provide detailed clinical data on inflammatory and other biomarkers obtained from patients after acute knee trauma in order to (i) present a timeline of events that occur in the acute, subacute, and chronic post-traumatic phases and in PTOA, and (ii) to identify key factors present in the synovial fluid, serum/plasma and urine, leading to PTOA of the knee in 23-50% of individuals who had acute knee trauma. In this context, we additionally discuss methods of simulating knee trauma and inflammation in in vivo, ex vivo articular cartilage explant and in vitro chondrocyte models, and answer whether these models are representative of the clinical inflammatory stages following knee trauma. Moreover, we compare the pro-inflammatory cytokine concentrations used in such models and demonstrate that, compared to concentrations in the synovial fluid after knee trauma, they are exceedingly high. We then used the Bradford Hill Framework to present evidence that TNF-α and IL-6 cytokines are causal factors, while IL-1β and IL-17 are credible factors in inducing knee PTOA disease progresssion. Lastly, we discuss beneficial infrastructure for future studies to dissect the role of local vs. systemic inflammation in PTOA progression with an emphasis on early disease.
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Affiliation(s)
| | | | | | | | - Melanie L. Hart
- G.E.R.N. Center for Tissue Replacement, Regeneration & Neogenesis, Department of Orthopedics and Trauma Surgery, Faculty of Medicine, Medical Center—Albert-Ludwigs-University of Freiburg, 79085 Freiburg im Breisgau, Germany; (C.M.K.); (R.A.); (J.M.H.); (B.R.)
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