The role of the lymphatic system in musculoskeletal system health and disease: research progress and future directions

Abstract

The lymphatic system is widely distributed in skeletal muscles, joints, and skeletal tissues and plays a key role in maintaining immune homeostasis, regulating inflammatory responses, and tissue repair. In recent years, an increasing number of studies have shown that morphological and functional changes in lymphatic vessels are closely associated with the onset and progression of a variety of musculoskeletal disorders (MSDs), such as osteoarthritis (OA), fractures, and muscular dystrophy. However, the specific mechanisms of the lymphatic system’s role in these diseases have not been fully elucidated, and their potential clinical value remains to be thoroughly explored. In this review, we review the recent research progress on the structure, function, and pathophysiological role of the lymphatic system in the musculoskeletal system, and we focus on the association between lymphangiogenesis, dysfunction, and MSDs, and systematically summarize the therapeutic strategies targeting the lymphatic system. In addition, we summarize the limitations of current studies and propose key directions for future research, with a view to providing new ideas for basic research and clinical intervention in MSDs.

References

[1] Rauniyar K, Jha SK, Jeltsch M. Biology of Vascular Endothelial Growth Factor C in the morphogenesis of lymphatic vessels. Front Bioeng. Biotechnol., 2018, 6: 7

[2] Edwards JR, et al.. Lymphatics and bone. Hum. Pathol., 2008, 39: 49-55

[3] Breslin JW, et al.. Lymphatic vessel network structure and physiology. Compr. Physiol., 2018, 9: 207-299

[4] Iizuka K, Machida T, Hirafuji M. Skeletal muscle is an endocrine organ. J. Pharm. Sci., 2014, 125: 125-131

[5] Gomez-Galan M, Perez-Alonso J, Callejon-Ferre AJ, Lopez-Martinez J. Musculoskeletal disorders: OWAS review. Ind. Health, 2017, 55: 314-337

[6] Lidgren L. The Bone and Joint Decade and the global economic and healthcare burden of musculoskeletal disease. J. Rheumatol. Suppl., 2003, 67: 4-5

[7] Cao F, et al.. Trends and cross-country inequalities in the global burden of osteoarthritis, 1990-2019: A population-based study. Ageing Res. Rev., 2024, 99: 102382

[8] Zhou S, et al.. Lymphatic vessels: roles and potential therapeutic intervention in rheumatoid arthritis and osteoarthritis. Theranostics, 2024, 14: 265-282

[9] Solorzano E, et al.. Osteopathy in Complex Lymphatic Anomalies. Int. J. Mol. Sci, 2022, 23: 8258

[10] Ji RC. Recent advances and new insights into muscular lymphangiogenesis in health and disease. Life Sci., 2018, 211: 261-269

[11] Ji RC, Eshita Y, Xing L, Miura M. Multiple expressions of lymphatic markers and morphological evolution of newly formed lymphatics in lymphangioma and lymph node lymphangiogenesis. Microvasc. Res., 2010, 80: 195-201

[12] Xu H, et al.. Distribution of lymphatic vessels in normal and arthritic human synovial tissues. Ann. Rheum. Dis., 2003, 62: 1227-1229

[13] Liang QQ, Shi Q, Wood RW, Xing LP, Wang YJ. Peri-articular lymphatic system and “Bi” theory of Chinese medicine in the pathogenesis and treatment of arthritis. Chin. J. Integr. Med., 2015, 21: 648-655

[14] Biswas L, et al.. Lymphatic vessels in bone support regeneration after injury. Cell, 2023, 186: 382-397.e324

[15] Zou F, et al.. Revealing the presence of lymphatic vessels within intervertebral discs: Novel insights into disc degeneration. Innovation, 2025, 6: 100865

[16] Cao M, Ong MTY, Yung PSH, Tuan RS, Jiang Y. Role of synovial lymphatic function in osteoarthritis. Osteoarthr. Cartil., 2022, 30: 1186-1197

[17] Shi J, et al.. Distribution and alteration of lymphatic vessels in knee joints of normal and osteoarthritic mice. Arthritis Rheumatol., 2014, 66: 657-666

[18] Shi JX, et al.. Use of a whole-slide imaging system to assess the presence and alteration of lymphatic vessels in joint sections of arthritic mice. Biotech. Histochem, 2013, 88: 428-439

[19] Hou T, et al.. Ginsenoside Rg1 promotes lymphatic drainage and improves chronic inflammatory arthritis. J. Musculoskelet. Neuronal Interact., 2020, 20: 526-534

[20] Skandalakis JE, Skandalakis LJ, Skandalakis PN. Anatomy of the lymphatics. Surg. Oncol. Clin. N. Am., 2007, 16: 1-16

[21] Yang Y, Oliver G. Development of the mammalian lymphatic vasculature. J. Clin. Invest, 2014, 124: 888-897

[22] Srinivasan RS, et al.. Lineage tracing demonstrates the venous origin of the mammalian lymphatic vasculature. Genes Dev., 2007, 21: 2422-2432

[23] Riquet M, Le Pimpec Barthes F, Souilamas R, Hidden G. Thoracic duct tributaries from intrathoracic organs. Ann. Thorac. Surg., 2002, 73: 892-898 discussion 898–899

[24] Rovenska E, Rovensky J. Lymphatic vessels: structure and function. Isr. Med Assoc. J., 2011, 13: 762-768

[25] Fischer M, et al.. Flow velocity of single lymphatic capillaries in human skin. Am. J. Physiol., 1996, 270: H358-H363

[26] Castenholz, A. Morphological characteristics of initial lymphatics in the tongue as shown by scanning electron microscopy. Scan Electron. Microsc. 1343–1352 (1984).

[27] Leak LV, Burke JF. Fine structure of the lymphatic capillary and the adjoining connective tissue area. Am. J. Anat., 1966, 118: 785-809

[28] Leak LV, Burke JF. Ultrastructural studies on the lymphatic anchoring filaments. J. Cell Biol., 1968, 36: 129-149

[29] Banerji S, et al.. LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J. Cell Biol., 1999, 144: 789-801

[30] Noda Y, Amano I, Hata M, Kojima H, Sawa Y. Immunohistochemical examination on the distribution of cells expressed lymphatic endothelial marker podoplanin and LYVE-1 in the mouse tongue tissue. Acta Histochem Cytochem, 2010, 43: 61-68

[31] Breiteneder-Geleff S, et al.. Podoplanin, novel 43-kd membrane protein of glomerular epithelial cells, is down-regulated in puromycin nephrosis. Am. J. Pathol., 1997, 151: 1141-1152

[32] Wigle JT, et al.. An essential role for Prox1 in the induction of the lymphatic endothelial cell phenotype. EMBO J., 2002, 21: 1505-1513

[33] Jeltsch M, et al.. Hyperplasia of lymphatic vessels in VEGF-C transgenic mice. Science, 1997, 276: 1423-1425

[34] Jussila L, et al.. Lymphatic endothelium and Kaposi’s sarcoma spindle cells detected by antibodies against the vascular endothelial growth factor receptor-3. Cancer Res., 1998, 58: 1599-1604

[35] Kaipainen A, et al.. Expression of the fms-like tyrosine kinase 4 gene becomes restricted to lymphatic endothelium during development. Proc. Natl. Acad. Sci. USA, 1995, 92: 3566-3570

[36] Kenney HM, et al.. The enigmas of lymphatic muscle cells: where do they come from, how are they maintained, and can they regenerate?. Curr. Rheumatol. Rev., 2023, 19: 246-259

[37] Zawieja DC. Contractile physiology of lymphatics. Lymphat Res. Biol., 2009, 7: 87-96

[38] Schulte-Merker S, Sabine A, Petrova TV. Lymphatic vascular morphogenesis in development, physiology, and disease. J. Cell Biol., 2011, 193: 607-618

[39] Schmid-Schonbein GW. Microlymphatics and lymph flow. Physiol. Rev., 1990, 70: 987-1028

[40] Zawieja D. Lymphatic biology and the microcirculation: past, present and future. Microcirculation, 2005, 12: 141-150

[41] von der Weid PY, Zawieja DC. Lymphatic smooth muscle: the motor unit of lymph drainage. Int. J. Biochem Cell Biol., 2004, 36: 1147-1153

[42] Causey L, Cowin SC, Weinbaum S. Quantitative model for predicting lymph formation and muscle compressibility in skeletal muscle during contraction and stretch. Proc. Natl. Acad. Sci. USA, 2012, 109: 9185-9190

[43] Permanyer M, Bošnjak B, Förster R. Dendritic cells, T cells and lymphatics: dialogues in migration and beyond. Curr. Opin. Immunol., 2018, 53: 173-179

[44] Lucas ED, Tamburini BAJ. Lymph node lymphatic endothelial cell expansion and contraction and the programming of the immune response. Front. Immunol., 2019, 10: 36

[45] Olate-Briones A, et al.. The meningeal lymphatic vasculature in neuroinflammation. Faseb j., 2022, 36: e22276

[46] Petrova TV, Koh GY. Biological functions of lymphatic vessels. Science, 2020, 369: eaax4063

[47] Stritt S, Koltowska K, Makinen T. Homeostatic maintenance of the lymphatic vasculature. Trends Mol. Med., 2021, 27: 955-970

[48] Ma W, et al.. Mitochondrial respiration controls the Prox1-Vegfr3 feedback loop during lymphatic endothelial cell fate specification and maintenance. Sci. Adv, 2021, 7: eabe7359

[49] Petrova TV, Koh GY. Organ-specific lymphatic vasculature: From development to pathophysiology. J. Exp. Med., 2018, 215: 35-49

[50] Oliver G, Kipnis J, Randolph GJ, Harvey NL. The lymphatic vasculature in the 21(st) century: novel functional roles in homeostasis and disease. Cell, 2020, 182: 270-296

[51] Alitalo K. The lymphatic vasculature in disease. Nat. Med., 2011, 17: 1371-1380

[52] Bovay E, et al.. Multiple roles of lymphatic vessels in peripheral lymph node development. J. Exp. Med., 2018, 215: 2760-2777

[53] Srinivasan RS, et al.. The Prox1-Vegfr3 feedback loop maintains the identity and the number of lymphatic endothelial cell progenitors. Genes Dev., 2014, 28: 2175-2187

[54] Wang Y, Oliver G. Current views on the function of the lymphatic vasculature in health and disease. Genes Dev., 2010, 24: 2115-2126

[55] Ahn JH, et al.. Meningeal lymphatic vessels at the skull base drain cerebrospinal fluid. Nature, 2019, 572: 62-66

[56] Ulvmar MH, Mäkinen T. Heterogeneity in the lymphatic vascular system and its origin. Cardiovasc Res, 2016, 111: 310-321

[57] Magold AI, Swartz MA. Pathogenic exploitation of lymphatic vessels. Cells, 2022, 11: 979

[58] Betterman KL, Harvey NL. The lymphatic vasculature: development and role in shaping immunity. Immunol. Rev., 2016, 271: 276-292

[59] Padera TP, Meijer EF, Munn LL. The lymphatic system in disease processes and cancer progression. Annu. Rev. Biomed. Eng., 2016, 18: 125-158

[60] Adair TH, Guyton AC. Modification of lymph by lymph nodes. II. Effect of increased lymph node venous blood pressure. Am. J. Physiol., 1983, 245: H616-H622

[61] Adair TH, Moffatt DS, Paulsen AW, Guyton AC. Quantitation of changes in lymph protein concentration during lymph node transit. Am. J. Physiol., 1982, 243: H351-H359

[62] Hay JB, Andrade WN. Lymphocyte recirculation, exercise, and immune responses. Can. J. Physiol. Pharm., 1998, 76: 490-496

[63] Stingl J, Stembera O. Distribution and ultrastructure of the initial lymphatics of some skeletal muscles in the rat. Lymphology, 1974, 7: 160-168

[64] Skalak TC, Schmid-Schonbein GW, Zweifach BW. New morphological evidence for a mechanism of lymph formation in skeletal muscle. Microvasc. Res, 1984, 28: 95-112

[65] Havas E, et al.. Lymph flow dynamics in exercising human skeletal muscle as detected by scintography. J. Physiol., 1997, 504: 233-239

[66] Pan X, et al.. Activation of Nrf2/HO-1 signal with Myricetin for attenuating ECM degradation in human chondrocytes and ameliorating the murine osteoarthritis. Int Immunopharmacol., 2019, 75: 105742

[67] Doan TN, Bernard FC, McKinney JM, Dixon JB, Willett NJ. Endothelin-1 inhibits size dependent lymphatic clearance of PEG-based conjugates after intra-articular injection into the rat knee. Acta Biomater., 2019, 93: 270-281

[68] Bouta EM, et al.. Targeting lymphatic function as a novel therapeutic intervention for rheumatoid arthritis. Nat. Rev. Rheumatol., 2018, 14: 94-106

[69] Liang Q, et al.. Lymphatic muscle cells contribute to dysfunction of the synovial lymphatic system in inflammatory arthritis in mice. Arthritis Res. Ther., 2021, 23: 58

[70] Tong L, et al.. Current understanding of osteoarthritis pathogenesis and relevant new approaches. Bone Res., 2022, 10: 60

[71] Fuller KM, Munro RR. Lymphatic drainage of bone marrow. Aust. N. Z. J. Surg., 1964, 34: 11-14

[72] Greenbaum A, et al.. Bone CLARITY: Clearing, imaging, and computational analysis of osteoprogenitors within intact bone marrow. Sci. Transl. Med, 2017, 9: eaah6518

[73] Jing D, et al.. Tissue clearing of both hard and soft tissue organs with the PEGASOS method. Cell Res., 2018, 28: 803-818

[74] Smith RJ, Sage HH, Miyazaki M, Kizilay D. The relationship of lymphatics to bone. Bull. Hosp. Jt. Dis., 1960, 21: 25-41

[75] Griffie RA, Ecoiffier J. Demonstration of the lymphatics by intra-osseous injections. C. R. Hebd. Seances Acad. Sci., 1958, 246: 635-636

[76] Olszewski WL, Sawicki Z. Radiological evidence of lymphatic drainage of bone marrow cavity in long bones. Lymphology, 1977, 10: 1-4

[77] Vittas D, Hainau B. Lymphatic capillaries of the periosteum: do they exist?. Lymphology, 1989, 22: 173-177

[78] Lorenz M, Plenk HJr.. A perfusion method of incubation to demonstrate horseradish peroxidase in bone. Histochemistry, 1977, 53: 257-263

[79] Dillaman RM. Movement of ferritin in the 2-day-old chick femur. Anat. Rec., 1984, 209: 445-453

[80] Seliger WG. Tissue fluid movement in compact bone. Anat. Rec., 1970, 166: 247-255

[81] Montgomery RJ, Sutker BD, Bronk JT, Smith SR, Kelly PJ. Interstitial fluid flow in cortical bone. Microvasc. Res., 1988, 35: 295-307

[82] Bazantova I. The blood and lymph bed in Haversian bone. Folia Morphol., 1989, 37: 213-215

[83] Dillaman RM, Roer RD, Gay DM. Fluid movement in bone: theoretical and empirical. J. Biomech., 1991, 24: 163-177

[84] McCarter AL, et al.. Bone development and fracture healing is normal in mice that have a defect in the development of the lymphatic system. Lymphology, 2020, 53: 162-171

[85] Zheng Y, et al.. Lymphatic platelet thrombosis limits bone repair by precluding lymphatic transporting DAMPs. Nat. Commun., 2025, 16 829

[86] Kliskey K, et al.. The presence and absence of lymphatic vessels in the adult human intervertebral disc: relation to disc pathology. Skelet. Radio., 2009, 38: 1169-1173

[87] Rudert M, Tillmann B. Lymph and blood supply of the human intervertebral disc. Cadaver study of correlations to discitis. Acta Orthop. Scand., 1993, 64: 37-40

[88] Khadanovich A, et al.. Anatomy of the diaphragmatic crura and other paraspinal structures relevant to en-bloc spondylectomy for lumbar spine tumours. Eur. Spine J, 2025, 34: 3532-3539

[89] Fu Y, et al.. The paravertebral lymphatic system is involved in the resorption of the herniated nucleus pulposus and the regression of inflammation associated with disc herniation. Osteoarthr. Cartil., 2024, 32: 1566-1578

[90] Lin M, et al.. Machine learning-based diagnostic model of lymphatics-associated genes for new therapeutic target analysis in intervertebral disc degeneration. Front. Immunol., 2024, 15: 1441028

[91] Smolen JS, et al.. Rheumatoid arthritis. Nat. Rev. Dis. Prim., 2018, 4: 18001

[92] O’Byrne AM, et al.. Divergent gene signatures and neutrophil enrichment in lymph nodes of inflammatory arthritis patients. Arthritis Res. Ther., 2025, 27: 94

[93] Chen Y, et al.. The pro-inflammatory cytokine TNF-α inhibits lymphatic pumping via activation of the NF-κB-iNOS signaling pathway. Microcirculation, 2017, 24: 10.1111

[94] Shibuya M, Claesson-Welsh L. Signal transduction by VEGF receptors in regulation of angiogenesis and lymphangiogenesis. Exp. Cell Res., 2006, 312: 549-560

[95] Wauke K, Nagashima M, Ishiwata T, Asano G, Yoshino S. Expression and localization of vascular endothelial growth factor-C in rheumatoid arthritis synovial tissue. J. Rheumatol., 2002, 29: 34-38

[96] Zhou Q, Wood R, Schwarz EM, Wang YJ, Xing L. Near-infrared lymphatic imaging demonstrates the dynamics of lymph flow and lymphangiogenesis during the acute versus chronic phases of arthritis in mice. Arthritis Rheum., 2010, 62: 1881-1889

[97] Li J, et al.. Expanded CD23⁺/CD21^hi B cells in inflamed lymph nodes are associated with the onset of inflammatory-erosive arthritis in TNF-transgenic mice and are targets of anti-CD20 therapy. J. Immunol., 2010, 184: 6142-6150

[98] Zhang Q, et al.. Increased lymphangiogenesis in joints of mice with inflammatory arthritis. Arthritis Res. Ther., 2007, 9: R118

[99] Scallan JP, et al.. Ex vivo demonstration of functional deficiencies in popliteal lymphatic vessels from TNF-transgenic mice with inflammatory arthritis. Front Physiol., 2021, 12: 745096

[100] Bell RD, et al.. iNOS dependent and independent phases of lymph node expansion in mice with TNF-induced inflammatory-erosive arthritis. Arthritis Res. Ther., 2019, 21: 240

[101] Guo R, et al.. Inhibition of lymphangiogenesis and lymphatic drainage via vascular endothelial growth factor receptor 3 blockade increases the severity of inflammation in a mouse model of chronic inflammatory arthritis. Arthritis Rheum., 2009, 60: 2666-2676

[102] Li P, et al.. Systemic tumor necrosis factor alpha mediates an increase in peripheral CD11bhigh osteoclast precursors in tumor necrosis factor alpha-transgenic mice. Arthritis Rheum., 2004, 50: 265-276

[103] Watari K, et al.. Role of macrophages in inflammatory lymphangiogenesis: Enhanced production of vascular endothelial growth factor C and D through NF-kappaB activation. Biochem. Biophys. Res. Commun., 2008, 377: 826-831

[104] Walsh DA, et al.. Lymphatic vessels in osteoarthritic human knees. Osteoarthr. Cartil., 2012, 20: 405-412

[105] Scanzello CR. Role of low-grade inflammation in osteoarthritis. Curr. Opin. Rheumatol., 2017, 29: 79-85

[106] Michalaki E, et al.. Effect of human synovial fluid from osteoarthritis patients and healthy individuals on lymphatic contractile activity. J. Biomech. Eng, 2022, 144: 071012

[107] Lin X, et al.. Targeting synovial lymphatic function as a novel therapeutic intervention for age-related osteoarthritis in mice. Arthritis Rheumatol., 2023, 75: 923-936

[108] Zhou C, Sun T, Dong Z, Lu F, Li B. The interplay between lymphatic vessels and macrophages in inflammation response. FASEB J., 2024, 38: e23879

[109] Wheeler TA, et al.. Mechanical loading of joint modulates T cells in lymph nodes to regulate osteoarthritis. Osteoarthr. Cartil., 2024, 32: 287-298

[110] de Jesus FN, von der Weid PY. Increased contractile activity and dilation of popliteal lymphatic vessels in the TNF-α-overexpressing TNF(ΔARE/+) arthritic mouse. Life Sci., 2023, 335: 122247

[111] Pal S, Meininger CJ, Gashev AA. Aged Lymphatic Vessels and Mast Cells in Perilymphatic Tissues. Int. J. Mol. Sci, 2017, 18: 965

[112] Kenney HM, et al.. Persistent popliteal lymphatic muscle cell coverage defects despite amelioration of arthritis and recovery of popliteal lymphatic vessel function in TNF-Tg mice following anti-TNF therapy. Sci. Rep., 2022, 12 12751

[113] Song X, et al.. An injectable thermosensitive hydrogel delivering M2 macrophage-derived exosomes alleviates osteoarthritis by promoting synovial lymphangiogenesis. Acta Biomater., 2024, 189: 130-142

[114] Wang W, et al.. Attenuated joint tissue damage associated with improved synovial lymphatic function following treatment with Bortezomib in a mouse model of experimental posttraumatic Osteoarthritis. Arthritis Rheumatol., 2019, 71: 244-257

[115] Grillet B, et al.. Matrix metalloproteinases in arthritis: towards precision medicine. Nat. Rev. Rheumatol., 2023, 19: 363-377

[116] Mobasheri A, et al.. The role of metabolism in the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol., 2017, 13: 302-311

[117] Kormano M, Makela P. Lymphatics filled at knee arthrography. Acta Radio. Diagn., 1978, 19: 853-858

[118] Wallis WJ, Simkin PA, Nelp WB, Foster DM. Intraarticular volume and clearance in human synovial effusions. Arthritis Rheum., 1985, 28: 441-449

[119] Li Z, Tian Y. Role of NEL‑like molecule‑1 in osteogenesis/chondrogenesis (Review). Int. J. Mol. Med, 2025, 55: 5

[120] Bi J, et al.. Age-related bone diseases: Role of inflammaging. J. Autoimmun., 2024, 143: 103169

[121] Vishlaghi N, et al.. Vegfc-expressing cells form heterotopic bone after musculoskeletal injury. Cell Rep., 2024, 43: 114049

[122] Lips KS, et al.. Podoplanin immunopositive lymphatic vessels at the implant interface in a rat model of osteoporotic fractures. PLoS One, 2013, 8: e77259

[123] Zhao C, et al.. Preventing periprosthetic osteolysis in aging populations through lymphatic activation and stem cell-associated secretory phenotype inhibition. Commun. Biol., 2024, 7: 962

[124] Zheng Y, et al.. A novel therapy for fracture healing by increasing lymphatic drainage. J. Orthop. Transl., 2024, 45: 66-74

[125] Qin Z, et al.. Targeting endoplasmic reticulum stress-induced lymphatic dysfunction for mitigating bisphosphonate-related osteonecrosis. Clin. Transl. Med, 2024, 14 e70082

[126] Tanoue R, Koi K, Yamashita J. Effect of Alendronate on bone formation during tooth extraction wound healing. J. Dent. Res, 2015, 94: 1251-1258

[127] Nozawa A, et al.. A somatic activating KRAS variant identified in an affected lesion of a patient with Gorham-Stout disease. J. Hum. Genet., 2020, 65: 995-1001

[128] Rodriguez-Laguna L, et al.. Somatic activating mutations in PIK3CA cause generalized lymphatic anomaly. J. Exp. Med., 2019, 216: 407-418

[129] Manevitz-Mendelson E, et al.. Somatic NRAS mutation in patient with generalized lymphatic anomaly. Angiogenesis, 2018, 21: 287-298

[130] Liu Y, et al.. Gorham-Stout disease: radiological, histological, and clinical features of 12 cases and review of literature. Clin. Rheumatol., 2016, 35: 813-823

[131] Gorham LW, Stout AP. Massive osteolysis (acute spontaneous absorption of bone, phantom bone, disappearing bone); its relation to hemangiomatosis. J. Bone Jt. Surg. Am., 1955, 37-A: 985-1004

[132] Kato H, Ozeki M, Fukao T, Matsuo M. MR imaging findings of vertebral involvement in Gorham-Stout disease, generalized lymphatic anomaly, and kaposiform lymphangiomatosis. Jpn J. Radio., 2017, 35: 606-612

[133] Ricci KW, Iacobas I. How we approach the diagnosis and management of complex lymphatic anomalies. Pediatr. Blood Cancer, 2022, 69: e28985

[134] Fernandes LM, et al.. Hyperactive KRAS/MAPK signaling disrupts normal lymphatic vessel architecture and function. Front. Cell Dev. Biol., 2023, 11: 1276333

[135] Monroy M, McCarter AL, Hominick D, Cassidy N, Dellinger MT. Lymphatics in bone arise from pre-existing lymphatics. Development, 2020, 147: dev184291

[136] McCarter AL, Dellinger MT. Trametinib inhibits lymphatic vessel invasion of bone in a mouse model of Gorham-Stout disease. J. Vasc. Anom, 2023, 4: e070

[137] Ricci KW, et al.. Efficacy of systemic sirolimus in the treatment of generalized lymphatic anomaly and Gorham-Stout disease. Pediatr. Blood Cancer, 2019, 66: e27614

[138] Trenor CC3rd, Chaudry G. Complex lymphatic anomalies. Semin Pediatr. Surg., 2014, 23: 186-190

[139] Kuwahara G, Nishinakamura H, Kojima D, Tashiro T, Kodama S. Vascular endothelial growth factor-C derived from CD11b+ cells induces therapeutic improvements in a murine model of hind limb ischemia. J. Vasc. Surg., 2013, 57: 1090-1099

[140] Qin X, et al.. In situ size amplification strategy reduces lymphatic clearance for enhanced arthritis therapy. J. Nanobiotechnol., 2024, 22 755

[141] Homayun-Sepehr N, et al.. KRAS-driven model of Gorham-Stout disease effectively treated with trametinib. JCI Insight, 2021, 6: e149831

[142] Zhang D, et al.. Targeting local lymphatics to ameliorate heterotopic ossification via FGFR3-BMPR1a pathway. Nat. Commun., 2021, 12 4391

[143] Moriondo A, Solari E, Marcozzi C, Negrini D. Diaphragmatic lymphatic vessel behavior during local skeletal muscle contraction. Am. J. Physiol. Heart Circ. Physiol., 2015, 308: H193-H205

[144] Mazzoni MC, Skalak TC, Schmid-Schonbein GW. Effects of skeletal muscle fiber deformation on lymphatic volumes. Am. J. Physiol., 1990, 259: H1860-H1868

[145] Taketa Y, et al.. Lymphatic capillarization in different fiber types of rat skeletal muscles with growth and age. Microcirculation, 2024, 31: e12879

[146] Cocks M, Wagenmakers AJ. The effect of different training modes on skeletal muscle microvascular density and endothelial enzymes controlling NO availability. J. Physiol., 2016, 594: 2245-2257

[147] Coates G, O’Brodovich H, Goeree G. Hindlimb and lung lymph flows during prolonged exercise. J. Appl Physiol. (1985), 1993, 75: 633-638

[148] Lu X, et al.. Cranial bone maneuver ameliorates Alzheimer’s disease pathology via enhancing meningeal lymphatic drainage function. Alzheimers Dement, 2025, 21: e14518

[149] Yeo KP, Lim HY, Angeli V. Leukocyte Trafficking via Lymphatic Vessels in Atherosclerosis. Cells, 2021, 10: 1344

[150] González-Loyola A, Petrova TV. Development and aging of the lymphatic vascular system. Adv. Drug Deliv. Rev., 2021, 169: 63-78

[151] Duan M, et al.. Preparation of the biodegradable lymphatic targeting imaging agent based on the indocyanine green mesoporous silicon system. Front Chem., 2022, 10: 847929

[152] Huo S, et al.. Epigenetic regulations of cellular senescence in osteoporosis. Ageing Res. Rev., 2024, 99: 102235

[153] Zhao J, et al.. Bmi-1 epigenetically orchestrates osteogenic and adipogenic differentiation of bone marrow mesenchymal stem cells to delay bone aging. Adv. Sci., 2024, 11: e2404518

[154] Boueya IL, Sandhow L, Albuquerque JRP, Znaidi R, Passaro D. Endothelial heterogeneity in bone marrow: insights across development, adult life and leukemia. Leukemia, 2025, 39: 8-24

[155] Davis MJ, Zawieja SD, King PD. Transport and immune functions of the lymphatic system. Annu Rev. Physiol., 2025, 87: 151-172

[156] Bano F, et al.. Structure and unusual binding mechanism of the hyaluronan receptor LYVE-1 mediating leucocyte entry to lymphatics. Nat. Commun., 2025, 16 2754

[157] Sanchez-Lopez E, Coras R, Torres A, Lane NE, Guma M. Synovial inflammation in osteoarthritis progression. Nat. Rev. Rheumatol., 2022, 18: 258-275

[158] Dainese P, et al.. Association between knee inflammation and knee pain in patients with knee osteoarthritis: a systematic review. Osteoarthr. Cartil., 2022, 30: 516-534

[159] Robinson WH, et al.. Low-grade inflammation as a key mediator of the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol., 2016, 12: 580-592

[160] Schuster R, Rockel JS, Kapoor M, Hinz B. The inflammatory speech of fibroblasts. Immunol. Rev., 2021, 302: 126-146

[161] Kakei Y, Akashi M, Shigeta T, Hasegawa T, Komori T. Alteration of cell-cell junctions in cultured human lymphatic endothelial cells with inflammatory cytokine stimulation. Lymphat. Res. Biol., 2014, 12: 136-143

[162] Huh YM, et al.. The role of popliteal lymph nodes in differentiating rheumatoid arthritis from osteoarthritis by using CE 3D FSPGR MR imaging: relationship of the inflamed synovial volume. Korean J. Radio., 2005, 6: 117-124

[163] Manferdini C, et al.. Adipose stromal cells mediated switching of the pro-inflammatory profile of M1-like macrophages is facilitated by PGE2: in vitro evaluation. Osteoarthr. Cartil., 2017, 25: 1161-1171

[164] Zhang Q, et al.. VEGF-C, a lymphatic growth factor, is a RANKL target gene in osteoclasts that enhances osteoclastic bone resorption through an autocrine mechanism. J. Biol. Chem., 2008, 283: 13491-13499

[165] Bouta EM, et al.. Brief Report: Treatment of tumor necrosis factor-transgenic mice with anti-tumor necrosis factor restores lymphatic contractions, repairs lymphatic vessels, and may increase monocyte/macrophage Egress. Arthritis Rheumatol., 2017, 69: 1187-1193

[166] Aldrich MB, et al.. Lymphatic delivery of etanercept via nanotopography improves response to collagen-induced arthritis. Arthritis Res. Ther., 2017, 19: 116

[167] Polomska AK, Proulx ST. Imaging technology of the lymphatic system. Adv. Drug Deliv. Rev., 2021, 170: 294-311

[168] Zhang F, et al.. Defining inflammatory cell states in rheumatoid arthritis joint synovial tissues by integrating single-cell transcriptomics and mass cytometry. Nat. Immunol., 2019, 20: 928-942

[169] Kuang L, et al.. FGFR3 deficiency enhances CXCL12-dependent chemotaxis of macrophages via upregulating CXCR7 and aggravates joint destruction in mice. Ann. Rheum. Dis., 2020, 79: 112-122

[170] Klaourakis K, Vieira JM, Riley PR. The evolving cardiac lymphatic vasculature in development, repair and regeneration. Nat. Rev. Cardiol., 2021, 18: 368-379

Funding

National Natural Science Foundation of China (National Science Foundation of China)(82272611, 82072506, 92268115, 82472522)

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The Author(s)