强直性脊柱炎骨代谢的研究进展
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摘要
强直性脊柱炎(ankylosing spondylitis,AS)是一种自身免疫功能异常引起的以慢性炎症性关节炎为主要表现的疾病,可发展为脊柱关节炎,慢性炎症和病理性骨形成是它的两个主要病理特点。进行性的脊柱关节僵硬引起的脊柱活动障碍是患者最常见的主诉,因此对脊柱关节的异常骨增生的病理机制得到广泛的关注。但随着对AS研究的深入,发现在脊柱局部过度骨化的同时伴有系统性的骨丢失,表明AS发病过程不仅仅是单一的成骨或破骨异常,而是处于兼有两者的骨代谢失衡环境中。目前研究发现AS疾病中Wnt、BMP信号通路和炎症反应在AS疾病中既促进成骨,又能影响破骨细胞形成;而破骨细胞在发挥骨吸收作用的同时,它的产物又参与了新生骨形成。但大多数研究均是着重于描述单独的成骨或破骨机制,未能明确地阐明它们是如何在引起脊柱周围骨质增生的同时导致全身骨量丢失的具体作用机制。AS病理过程中炎症因子是否在不同的部位发挥不同的作用,如何在控制新生骨形成的同时减少骨质疏松发生的风险,这些问题仍需要得到进一步的探索研究。
Ankylosing spondylitis(AS) is a disease characterized by chronic inflammatory arthritis caused by abnormal autoimmune function, which can develop into spinal arthritis. Chronic inflammation and pathological bone formation are its two main pathological features. Progressive spinal dyskinesia is the most important complaint in patients. So the pathological mechanism of abnormal osseous hyperplasia of the spinal joint is widely concerned. However, with the further study of AS, it is found that partial ossification of the spinal column often accompanied by systemic bone loss. This indicated that pathogenesis of AS is not due to the occurrence of abnormal osteogenesis or bone resorption alone, but because of an unbalanced environment of bone metabolism with both. Recent studies have shown Wnt, BMP signaling pathway and inflammatory reaction in AS disease not only promote osteogenesis, but also affect osteoclast formation. Nevertheless osteoclast plays a role in bone resorption, while its products participate in new bone formation. However, most studies have only focused on describing a single mechanism of osteogenesis or osteoclasts in the AS, and have not clearly elucidated how they contribute to bone mass loss in the whole body while causing bone hyperplasia around the spine. In the pathological process of AS, whether the inflammatory factors play different roles in different parts of the body, and how to control the formation of new bone and reduce the risk of osteoporosis, need to be further explored.
Ankylosing spondylitis(AS) is a disease characterized by chronic inflammatory arthritis caused by abnormal autoimmune function, which can develop into spinal arthritis. Chronic inflammation and pathological bone formation are its two main pathological features. Progressive spinal dyskinesia is the most important complaint in patients. So the pathological mechanism of abnormal osseous hyperplasia of the spinal joint is widely concerned. However, with the further study of AS, it is found that partial ossification of the spinal column often accompanied by systemic bone loss. This indicated that pathogenesis of AS is not due to the occurrence of abnormal osteogenesis or bone resorption alone, but because of an unbalanced environment of bone metabolism with both. Recent studies have shown Wnt, BMP signaling pathway and inflammatory reaction in AS disease not only promote osteogenesis, but also affect osteoclast formation. Nevertheless osteoclast plays a role in bone resorption, while its products participate in new bone formation. However, most studies have only focused on describing a single mechanism of osteogenesis or osteoclasts in the AS, and have not clearly elucidated how they contribute to bone mass loss in the whole body while causing bone hyperplasia around the spine. In the pathological process of AS, whether the inflammatory factors play different roles in different parts of the body, and how to control the formation of new bone and reduce the risk of osteoporosis, need to be further explored.
引文
[1] 刘岗,颜华儒,许立新.颈椎小关节评估在改良型Stoke强直性脊柱炎脊柱评分体系中对评估强直性脊柱炎的影像学进展的研究[J].中国骨质疏松杂志,2018,24(1):20-24.
[2] Ronneberger M,Schett G.Pathophysiology of spondyloarthritis[J].Curr Rheumatol Rep,2011,13(5):416-420.
[3] Perpetuo IP,Raposeiro R,Caetano-Lopes J,et al.Effect of tumor necrosis factor inhibitor therapy on osteoclasts precursors in ankylosing spondylitis[J].PLoS One,2015,10(12):e0144655.
[4] Kobayashi Y,Uehara S,Udagawa N,et al.Regulation of bone metabolism by Wnt signals[J].J Biochem,2016,159(4):387-392.
[5] Karner CM,Long F.Wnt signaling and cellular metabolism in osteoblasts[J].Cell Mol Life Sci,2017,74(9):1649-1657.
[6] Klingberg E,Nurkkala M,Carlsten H,et al.Biomarkers of bone metabolism in ankylosing spondylitis in relation to osteoproliferation and osteoporosis[J].J Rheumatol,2014,41(7):1349-1356.
[7] Briolay A,Lencel P,Bessueille L,et al.Autocrine stimulation of osteoblast activity by Wnt5a in response to TNF-alpha in human mesenchymal stem cells[J].Biochem Biophys Res Commun,2013,430(3):1072-1077.
[8] Maeda K,Kobayashi Y,Udagawa N,et al.Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis[J].Nat Med,2012,18(3):405-412.
[9] Maeda K,Takahashi N,Kobayashi Y.Roles of Wnt signals in bone resorption during physiological and pathological states[J].J Mol Med (Berl),2013,91(1):15-23.
[10] 陈伟健,晋大祥,谢炜星,等.Runx2 基因参与骨代谢相关通路的研究进展[J].中国骨质疏松杂志,2018,24(4):557-560.
[11] Jo S,Kang S,Han J,et al.Accelerated osteogenic differentiation of human bone-derived cells in ankylosing spondylitis[J].J Bone Miner Metab,2017,6:1-7.
[12] Xie Z,Wang P,Li Y,et al.Imbalance between bone morphogenetic protein 2 and noggin induces abnormal osteogenic differentiation of mesenchymal stem cells in ankylosing spondylitis[J].Arthritis Rheumatol,2016,68(2):430-440.
[13] Yuan TL,Chen J,Tong YL,et al.Serum heme oxygenase-1 and BMP-7 are potential biomarkers for bone metabolism in patients with rheumatoid arthritis and ankylosing spondylitis[J].Biomed Res Int,2016,2016:7870925.
[14] Pray C,Feroz NI,Nigil Haroon N.Bone mineral density and fracture risk in ankylosing spondylitis:A meta-analysis[J].Calcif Tissue Int,2017,101(2):182-192.
[15] Korczowska I,Przepiera-Bedzak H,Brzosko M,et al.Bone tissue metabolism in men with ankylosing spondylitis[J].Adv Med Sci,2011,56(2):264-269.
[16] Yilmaz N,Ozaslan J.Biochemical bone turnover markers in patients with ankylosing spondylitis[J].Clin Rheumatol,2000,19(2):92-98.
[17] Liu KG,He QH,Tan JW,et al.Expression of TNF-alpha,VEGF,and MMP-3 mRNAs in synovial tissues and their roles in fibroblast-mediated osteogenesis in ankylosing spondylitis[J].Genet Mol Res,2015,14(2):6852-6858.
[18] Yang C,Ding P,Wang Q,et al.Inhibition of complement retards ankylosing spondylitis progression[J].Sci Rep,2016,6:34643.
[19] Lin S,Qiu M,Chen J.IL-4 modulates macrophage polarization in ankylosing spondylitis[J].Cell Physiol Biochem,2015,35(6):2213-2222.
[20] Slobodin G,Slobodin B,Rimar D,et al.Production of bone formation-regulating factors by osteoclasts in vitro does not correlate with the radiographic disease progression in patients with ankylosing spondylitis[J].Joint Bone Spine,2016,83(4):468-469.
[21] Duggan SN,Purcell C,Kilbane M,et al.An association between abnormal bone turnover,systemic inflammation,and osteoporosis in patients with chronic pancreatitis:a case-matched study[J].Am J Gastroenterol,2015,110(2):336-345.
[22] Gallo J,Raska M,Kriegova E,et al.Inflammation and its resolution and the musculoskeletal system[J].J Orthop Translat,2017,10:52-67.
[23] Collins FL,Williams JO,Bloom AC,et al.Death receptor 3 (TNFRSF25) increases mineral apposition by osteoblasts and region specific new bone formation in the axial skeleton of male DBA/1 mice[J].J Immunol Res,2015,2015:901679.
[24] Lee EJ,Lee EJ,Chung YH,et al.High level of interleukin-32 gamma in the joint of ankylosing spondylitis is associated with osteoblast differentiation[J].Arthritis Res Ther,2015,17:350.
[25] Bruijnen STG,Verweij NJF,van Duivenvoorde LM,et al.Bone formation in ankylosing spondylitis during anti-tumour necrosis factor therapy imaged by 18F-fluoride positron emission tomography[J].Rheumatology (Oxford),2018,57(4):631-638.
[26] Arends S,Spoorenberg A,Bruyn GA,et al.The relation between bone mineral density,bone turnover markers,and vitamin D status in ankylosing spondylitis patients with active disease:a cross-sectional analysis[J].Osteoporos Int,2011,22(5):1431-1439.
[2] Ronneberger M,Schett G.Pathophysiology of spondyloarthritis[J].Curr Rheumatol Rep,2011,13(5):416-420.
[3] Perpetuo IP,Raposeiro R,Caetano-Lopes J,et al.Effect of tumor necrosis factor inhibitor therapy on osteoclasts precursors in ankylosing spondylitis[J].PLoS One,2015,10(12):e0144655.
[4] Kobayashi Y,Uehara S,Udagawa N,et al.Regulation of bone metabolism by Wnt signals[J].J Biochem,2016,159(4):387-392.
[5] Karner CM,Long F.Wnt signaling and cellular metabolism in osteoblasts[J].Cell Mol Life Sci,2017,74(9):1649-1657.
[6] Klingberg E,Nurkkala M,Carlsten H,et al.Biomarkers of bone metabolism in ankylosing spondylitis in relation to osteoproliferation and osteoporosis[J].J Rheumatol,2014,41(7):1349-1356.
[7] Briolay A,Lencel P,Bessueille L,et al.Autocrine stimulation of osteoblast activity by Wnt5a in response to TNF-alpha in human mesenchymal stem cells[J].Biochem Biophys Res Commun,2013,430(3):1072-1077.
[8] Maeda K,Kobayashi Y,Udagawa N,et al.Wnt5a-Ror2 signaling between osteoblast-lineage cells and osteoclast precursors enhances osteoclastogenesis[J].Nat Med,2012,18(3):405-412.
[9] Maeda K,Takahashi N,Kobayashi Y.Roles of Wnt signals in bone resorption during physiological and pathological states[J].J Mol Med (Berl),2013,91(1):15-23.
[10] 陈伟健,晋大祥,谢炜星,等.Runx2 基因参与骨代谢相关通路的研究进展[J].中国骨质疏松杂志,2018,24(4):557-560.
[11] Jo S,Kang S,Han J,et al.Accelerated osteogenic differentiation of human bone-derived cells in ankylosing spondylitis[J].J Bone Miner Metab,2017,6:1-7.
[12] Xie Z,Wang P,Li Y,et al.Imbalance between bone morphogenetic protein 2 and noggin induces abnormal osteogenic differentiation of mesenchymal stem cells in ankylosing spondylitis[J].Arthritis Rheumatol,2016,68(2):430-440.
[13] Yuan TL,Chen J,Tong YL,et al.Serum heme oxygenase-1 and BMP-7 are potential biomarkers for bone metabolism in patients with rheumatoid arthritis and ankylosing spondylitis[J].Biomed Res Int,2016,2016:7870925.
[14] Pray C,Feroz NI,Nigil Haroon N.Bone mineral density and fracture risk in ankylosing spondylitis:A meta-analysis[J].Calcif Tissue Int,2017,101(2):182-192.
[15] Korczowska I,Przepiera-Bedzak H,Brzosko M,et al.Bone tissue metabolism in men with ankylosing spondylitis[J].Adv Med Sci,2011,56(2):264-269.
[16] Yilmaz N,Ozaslan J.Biochemical bone turnover markers in patients with ankylosing spondylitis[J].Clin Rheumatol,2000,19(2):92-98.
[17] Liu KG,He QH,Tan JW,et al.Expression of TNF-alpha,VEGF,and MMP-3 mRNAs in synovial tissues and their roles in fibroblast-mediated osteogenesis in ankylosing spondylitis[J].Genet Mol Res,2015,14(2):6852-6858.
[18] Yang C,Ding P,Wang Q,et al.Inhibition of complement retards ankylosing spondylitis progression[J].Sci Rep,2016,6:34643.
[19] Lin S,Qiu M,Chen J.IL-4 modulates macrophage polarization in ankylosing spondylitis[J].Cell Physiol Biochem,2015,35(6):2213-2222.
[20] Slobodin G,Slobodin B,Rimar D,et al.Production of bone formation-regulating factors by osteoclasts in vitro does not correlate with the radiographic disease progression in patients with ankylosing spondylitis[J].Joint Bone Spine,2016,83(4):468-469.
[21] Duggan SN,Purcell C,Kilbane M,et al.An association between abnormal bone turnover,systemic inflammation,and osteoporosis in patients with chronic pancreatitis:a case-matched study[J].Am J Gastroenterol,2015,110(2):336-345.
[22] Gallo J,Raska M,Kriegova E,et al.Inflammation and its resolution and the musculoskeletal system[J].J Orthop Translat,2017,10:52-67.
[23] Collins FL,Williams JO,Bloom AC,et al.Death receptor 3 (TNFRSF25) increases mineral apposition by osteoblasts and region specific new bone formation in the axial skeleton of male DBA/1 mice[J].J Immunol Res,2015,2015:901679.
[24] Lee EJ,Lee EJ,Chung YH,et al.High level of interleukin-32 gamma in the joint of ankylosing spondylitis is associated with osteoblast differentiation[J].Arthritis Res Ther,2015,17:350.
[25] Bruijnen STG,Verweij NJF,van Duivenvoorde LM,et al.Bone formation in ankylosing spondylitis during anti-tumour necrosis factor therapy imaged by 18F-fluoride positron emission tomography[J].Rheumatology (Oxford),2018,57(4):631-638.
[26] Arends S,Spoorenberg A,Bruyn GA,et al.The relation between bone mineral density,bone turnover markers,and vitamin D status in ankylosing spondylitis patients with active disease:a cross-sectional analysis[J].Osteoporos Int,2011,22(5):1431-1439.