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Hypertension meets osteoarthritis — revisiting the vascular aetiology hypothesis

Abstract

Osteoarthritis (OA) is a whole-joint disease characterized by subchondral bone perfusion abnormalities and neovascular invasion into the synovium and articular cartilage. In addition to local vascular disturbance, mounting evidence suggests a pivotal role for systemic vascular pathology in the aetiology of OA. This Review outlines the current understanding of the close relationship between high blood pressure (hypertension) and OA at the crossroads of epidemiology and molecular biology. As one of the most common comorbidities in patients with OA, hypertension can disrupt joint homeostasis both biophysically and biochemically. High blood pressure can increase intraosseous pressure and cause hypoxia, which in turn triggers subchondral bone and osteochondral junction remodelling. Furthermore, systemic activation of the renin–angiotensin and endothelin systems can affect the Wnt–β-catenin signalling pathway locally to govern joint disease. The intimate relationship between hypertension and OA indicates that endothelium-targeted strategies, including re-purposed FDA-approved antihypertensive drugs, could be useful in the treatment of OA.

Key points

  • Epidemiologically, high blood pressure (hypertension) has been linked to radiographic and symptomatic knee osteoarthritis.

  • At the tissue level, systemic hypertension leads to subchondral bone perfusion abnormalities and ischaemia, which disrupts angiogenic–osteogenic coupling and impairs the integrity of the bone–cartilage functional unit.

  • At the molecular level, systemic activation of the renin–angiotensin, endothelin and Wnt–β-catenin signalling pathways induces a phenotypical change in articular chondrocytes and triggers cartilage degradation.

  • Antihypertensive medications that exhibit chondroprotective effects in preclinical studies warrant further investigation in patients with osteoarthritis and the frequently encountered comorbidity of systemic hypertension.

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Fig. 1: The vasculature and its changes in knee osteoarthritis.
Fig. 2: Biophysical effects of hypertension on the joint at the cellular level.
Fig. 3: Molecular pathways shared by hypertension and osteoarthritis.

References

  1. Hunter, D. J., March, L. & Chew, M. Osteoarthritis in 2020 and beyond: a Lancet Commission. Lancet 396, 1711–1712 (2020).

    PubMed  Article  Google Scholar 

  2. Kendzerska, T. et al. The longitudinal relationship between hand, hip and knee osteoarthritis and cardiovascular events: a population-based cohort study. Osteoarthritis Cartilage 25, 1771–1780 (2017).

    CAS  PubMed  Article  Google Scholar 

  3. Haugen, I. K. et al. Hand osteoarthritis in relation to mortality and incidence of cardiovascular disease: data from the Framingham Heart Study. Ann. Rheum. Dis. 74, 74–81 (2015).

    PubMed  Article  Google Scholar 

  4. Nuesch, E. et al. All cause and disease specific mortality in patients with knee or hip osteoarthritis: population based cohort study. BMJ 342, d1165 (2011).

    PubMed  PubMed Central  Article  Google Scholar 

  5. Wallace, I. J. et al. Knee osteoarthritis has doubled in prevalence since the mid-20th century. Proc. Natl Acad. Sci. USA 114, 9332–9336 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  6. Zhang, Y.-M., Wang, J. & Liu, X.-G. Association between hypertension and risk of knee osteoarthritis: a meta-analysis of observational studies. Medicine 96, e7584 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  7. Xie, Y. et al. Metabolic syndrome, hypertension, and hyperglycemia were positively associated with knee osteoarthritis, while dyslipidemia showed no association with knee osteoarthritis. Clin. Rheumatol. 40, 711–724 (2021).

    PubMed  Article  Google Scholar 

  8. Wen, C. Y. et al. Bone loss at subchondral plate in knee osteoarthritis patients with hypertension and type 2 diabetes mellitus. Osteoarthritis Cartilage 21, 1716–1723 (2013).

    CAS  PubMed  Article  Google Scholar 

  9. Niu, J., Clancy, M., Aliabadi, P., Vasan, R. & Felson, D. T. Metabolic syndrome, its components, and knee osteoarthritis: The Framingham Osteoarthritis Study. Arthritis Rheumatol. 69, 1194–1203 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  10. Findlay, D. M. Vascular pathology and osteoarthritis. Rheumatology 46, 1763–1768 (2007).

    CAS  PubMed  Article  Google Scholar 

  11. Hussain, S. M. et al. Vascular pathology and osteoarthritis: a systematic review. J. Rheumatol. 47, 748–760 (2020).

    CAS  PubMed  Article  Google Scholar 

  12. Calvet, J. et al. High prevalence of cardiovascular co-morbidities in patients with symptomatic knee or hand osteoarthritis. Scand. J. Rheumatol. 45, 41–44 (2016).

    CAS  PubMed  Article  Google Scholar 

  13. Funck-Brentano, T., Nethander, M., Moverare-Skrtic, S., Richette, P. & Ohlsson, C. Causal factors for knee, hip and hand osteoarthritis: a Mendelian randomization study in the UK Biobank. Arthritis Rheumatol. 71, 1634–1641 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. Singh, G. et al. Consequences of increased systolic blood pressure in patients with osteoarthritis and rheumatoid arthritis. J. Rheumatol. 30, 714–719 (2003).

    PubMed  Google Scholar 

  15. Jamsen, E., Peltola, M., Eskelinen, A. & Lehto, M. U. Comorbid diseases as predictors of survival of primary total hip and knee replacements: a nationwide register-based study of 96 754 operations on patients with primary osteoarthritis. Ann. Rheum. Dis. 72, 1975–1982 (2012).

    PubMed  Article  Google Scholar 

  16. Lo, G. H. et al. Systolic and pulse pressure associate with incident knee osteoarthritis: data from the Osteoarthritis Initiative. Clin. Rheumatol. 36, 2121–2128 (2017).

    PubMed  PubMed Central  Article  Google Scholar 

  17. Ashmeik, W. et al. Association of blood pressure with knee cartilage composition and structural knee abnormalities: data from the Osteoarthritis Initiative. Skelet. Radiol. 49, 1359–1368 (2020).

    Article  Google Scholar 

  18. Lo, K., Au, M., Ni, J. & Wen, C. Association between hypertension and osteoarthritis: a systematic review and meta-analysis of observational studies. J. Orthop. Transl. https://doi.org/10.1016/j.jot.2021.05.003 (2021).

    Article  Google Scholar 

  19. Gandhi, R., Razak, F., Tso, P., Davey, J. R. & Mahomed, N. N. Asian ethnicity and the prevalence of metabolic syndrome in the osteoarthritic total knee arthroplasty population. J. Arthroplasty 25, 416–419 (2010).

    PubMed  Article  Google Scholar 

  20. Poornima, S., Subramanyam, K., Khan, I. A. & Hasan, Q. The insertion and deletion (I28005D) polymorphism of the angiotensin I converting enzyme gene is a risk factor for osteoarthritis in an Asian Indian population. J. Renin Angiotensin Aldosterone Syst. 16, 1281–1287 (2015).

    CAS  PubMed  Article  Google Scholar 

  21. Hong, S. J. et al. Angiotensin converting enzyme gene polymorphism in Korean patients with primary knee osteoarthritis. Exp. Mol. Med. 35, 189–195 (2003).

    CAS  PubMed  Article  Google Scholar 

  22. Lin, C. et al. Angiotensin-converting enzyme insertion/deletion polymorphism and susceptibility to osteoarthritis of the knee: a case-control study and meta-analysis. PLoS ONE 11, e0161754 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  23. Shehab, D. K. et al. Prevalence of angiotensin-converting enzyme gene insertion-deletion polymorphism in patients with primary knee osteoarthritis. Clin. Exp. Rheumatol. 26, 305–310 (2008).

    CAS  PubMed  Google Scholar 

  24. Smith, G. D. & Ebrahim, S. Mendelian randomization: prospects, potentials, and limitations. Int. J. Epidemiol. 33, 30–42 (2004).

    PubMed  Article  Google Scholar 

  25. Arnoldi, C. C. et al. Intraosseous hypertension and pain in the knee. J. Bone Joint Surg. Br. 57, 360–363 (1975).

    CAS  PubMed  Article  Google Scholar 

  26. Seah, S. et al. The relationship of tibial bone perfusion to pain in knee osteoarthritis. Osteoarthritis Cartilage 20, 1527–1533 (2012).

    CAS  PubMed  Article  Google Scholar 

  27. Ramasamy, S. K. et al. Blood flow controls bone vascular function and osteogenesis. Nat. Commun. 7, 13601 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  28. Zhen, G. et al. Inhibition of TGF-β signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis. Nat. Med. 19, 704–712 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  29. Grüneboom, A. et al. A network of trans-cortical capillaries as mainstay for blood circulation in long bones. Nat. Metab. 1, 236–250 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  30. Huber, M., Trattnig, S. & Lintner, F. Anatomy, biochemistry, and physiology of articular cartilage. Invest. Radiol. 35, 573–580 (2000).

    CAS  PubMed  Article  Google Scholar 

  31. Imhof, H. et al. Subchondral bone and cartilage disease: a rediscovered functional unit. Invest. Radiol. 35, 581–588 (2000).

    CAS  PubMed  Article  Google Scholar 

  32. Bashir, A., Gray, M. L., Boutin, R. D. & Burstein, D. Glycosaminoglycan in articular cartilage: in vivo assessment with delayed Gd (DTPA)(2-)-enhanced MR imaging. Radiology 205, 551–558 (1997).

    CAS  PubMed  Article  Google Scholar 

  33. Malinin, T. & Ouellette, E. Articular cartilage nutrition is mediated by subchondral bone: a long-term autograft study in baboons. Osteoarthritis Cartilage 8, 483–491 (2000).

    CAS  PubMed  Article  Google Scholar 

  34. Pan, J. et al. In situ measurement of transport between subchondral bone and articular cartilage. J. Orthop. Res. 27, 1347–1352 (2009).

    PubMed  PubMed Central  Article  Google Scholar 

  35. Arkill, K. & Winlove, C. Solute transport in the deep and calcified zones of articular cartilage. Osteoarthritis Cartilage 16, 708–714 (2008).

    CAS  PubMed  Article  Google Scholar 

  36. Lajeunesse, D. & Reboul, P. Subchondral bone in osteoarthritis: a biologic link with articular cartilage leading to abnormal remodeling. Curr. Opin. Rheumatol. 15, 628–633 (2003).

    PubMed  Article  Google Scholar 

  37. Lyons, T. J., McClure, S. F., Stoddart, R. W. & McClure, J. The normal human chondro-osseous junctional region: evidence for contact of uncalcified cartilage with subchondral bone and marrow spaces. BMC Musculoskelet. Disord. 7, 52 (2006).

    PubMed  PubMed Central  Article  Google Scholar 

  38. Sokoloff, L. Microcracks in the calcified layer of articular cartilage. Arch. Pathol. Lab. Med. 117, 191–195 (1993).

    CAS  PubMed  Google Scholar 

  39. Mori, S., Harruff, R. & Burr, D. Microcracks in articular calcified cartilage of human femoral heads. Arch. Pathol. Lab. Med. 117, 196–198 (1993).

    CAS  PubMed  Google Scholar 

  40. Knight, A. & Levick, J. R. Morphometry of the ultrastructure of the blood-joint barrier in the rabbit knee. Q. J. Exp. Physiol. 69, 271–288 (1984).

    CAS  PubMed  Article  Google Scholar 

  41. Knight, A. & Levick, J. R. The density and distribution of capillaries around a synovial cavity. Q. J. Exp. Physiol. 68, 629–644 (1983).

    CAS  PubMed  Article  Google Scholar 

  42. Walsh, D. et al. Lymphatic vessels in osteoarthritic human knees. Osteoarthritis Cartilage 20, 405–412 (2012).

    CAS  PubMed  Article  Google Scholar 

  43. Levick, J. Microvascular architecture and exchange in synovial joints. Microcirculation 2, 217–233 (1995).

    CAS  PubMed  Article  Google Scholar 

  44. Walsh, D. et al. Angiogenesis in the synovium and at the osteochondral junction in osteoarthritis. Osteoarthritis Cartilage 15, 743–751 (2007).

    CAS  PubMed  Article  Google Scholar 

  45. Lambert, C. et al. Characterization of synovial angiogenesis in osteoarthritis patients and its modulation by chondroitin sulfate. Arthritis Res. Ther. 14, R58 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  46. Lambert, C. et al. Gene expression pattern of cells from inflamed and normal areas of osteoarthritis synovial membrane. Arthritis Rheumatol. 66, 960–968 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  47. Giatromanolaki, A. et al. The angiogenic pathway “vascular endothelial growth factor/fl-1(KDR)-receptor” in rheumatoid arthritis and osteoarthritis. J. Pathol. 194, 101–108 (2001).

    CAS  PubMed  Article  Google Scholar 

  48. Haywood, L. et al. Inflammation and angiogenesis in osteoarthritis. Arthritis Rheum. 48, 2173–2177 (2003).

    CAS  PubMed  Article  Google Scholar 

  49. Trueta, J. & Harrison, M. The normal vascular anatomy of the femoral head in adult man. J. Bone Joint Surg. Br. 35, 442–461 (1953).

    PubMed  Article  Google Scholar 

  50. Morini, S., Pannarale, L., Conti, D. & Gaudio, E. Microvascular adaptation to growth in rat humeral head. Anat. Embryol. 211, 403–411 (2006).

    Article  Google Scholar 

  51. Clark, J. M. The structure of vascular channels in the subchondral plate. J. Anat. 171, 105–115 (1990).

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Lane, L. B., Villacin, A. & Bullough, P. The vascularity and remodelling of subchondrial bone and calcified cartilage in adult human femoral and humeral heads. An age- and stress-related phenomenon. J. Bone Joint Surg. Br. 59, 272–278 (1977).

    CAS  PubMed  Article  Google Scholar 

  53. Shibakawa, A. et al. The role of subchondral bone resorption pits in osteoarthritis: MMP production by cells derived from bone marrow. Osteoarthritis Cartilage 13, 679–687 (2005).

    CAS  PubMed  Article  Google Scholar 

  54. Suri, S. et al. Neurovascular invasion at the osteochondral junction and in osteophytes in osteoarthritis. Ann. Rheum. Dis. 66, 1423–1428 (2007).

    PubMed  PubMed Central  Article  Google Scholar 

  55. Burr, D. B. & Gallant, M. A. Bone remodelling in osteoarthritis. Nat. Rev. Rheumatol. 8, 665–673 (2012).

    CAS  PubMed  Article  Google Scholar 

  56. Harrison, M., Schajowicz, F. & Trueta, J. Osteoarthritis of the hip: a study of the nature and evolution of the disease. J. Bone Joint Surg. Br. 35, 598–626 (1953).

    PubMed  Article  Google Scholar 

  57. Boerckel, J. D., Uhrig, B. A., Willett, N. J., Huebsch, N. & Guldberg, R. E. Mechanical regulation of vascular growth and tissue regeneration in vivo. Proc. Natl Acad. Sci. USA 108, E674–E680 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  58. Hu, K. & Olsen, B. R. Osteoblast-derived VEGF regulates osteoblast differentiation and bone formation during bone repair. J. Clin. Invest. 126, 509–526 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  59. Liu, C. et al. Osteoblast-derived paracrine factors regulate angiogenesis in response to mechanical stimulation. Integr. Biol. 8, 785–794 (2016).

    CAS  Article  Google Scholar 

  60. Su, W. et al. Angiogenesis stimulated by elevated PDGF-BB in subchondral bone contributes to osteoarthritis development. JCI Insight 5, e135446 (2020).

    PubMed Central  Article  Google Scholar 

  61. Nagira, K. et al. Histological scoring system for subchondral bone changes in murine models of joint aging and osteoarthritis. Sci. Rep. 10, 10077 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  62. Bonde, H., Talman, M. & Kofoed, H. The area of the tidemark in osteoarthritis–a three–dimensional stereological study in 21 patients. APMIS 113, 349–352 (2005).

    CAS  PubMed  Article  Google Scholar 

  63. Walsh, D. A. et al. Angiogenesis and nerve growth factor at the osteochondral junction in rheumatoid arthritis and osteoarthritis. Rheumatology 49, 1852–1861 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  64. Hamilton, J. L. et al. Targeting VEGF and its receptors for the treatment of osteoarthritis and associated pain. J. Bone Miner. Res. 31, 911–924 (2016).

    PubMed  Article  Google Scholar 

  65. Cui, Z. et al. Halofuginone attenuates osteoarthritis by inhibition of TGF-β activity and H-type vessel formation in subchondral bone. Ann. Rheum. Dis. 75, 1714–1721 (2016).

    CAS  PubMed  Article  Google Scholar 

  66. Kusumbe, A. P., Ramasamy, S. K. & Adams, R. H. Coupling of angiogenesis and osteogenesis by a specific vessel subtype in bone. Nature 507, 323–328 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. Langen, U. H. et al. Cell–matrix signals specify bone endothelial cells during developmental osteogenesis. Nat. Cell Biol. 19, 189–201 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  68. Xie, H. et al. PDGF-BB secreted by preosteoclasts induces angiogenesis during coupling with osteogenesis. Nat. Med. 20, 1270–1278 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. Lu, J. et al. Positive-feedback regulation of subchondral H-type vessel formation by chondrocyte promotes osteoarthritis development in mice. J. Bone Miner. Res. 33, 909–920 (2018).

    CAS  PubMed  Article  Google Scholar 

  70. Watson, E. C. & Adams, R. H. Biology of bone: the vasculature of the skeletal system. Cold Spring Harb. Perspect. Med. 8, a031559 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  71. De Lorenzo, R. A., Ward, J. A., Jordan, B. S. & Hanson, C. E. Relationships of intraosseous and systemic pressure waveforms in a Swine model. Acad. Emerg. Med. 21, 899–904 (2014).

    PubMed  Article  Google Scholar 

  72. Beverly, M. & Murray, D. Factors affecting intraosseous pressure measurement. J. Orthop. Surg. Res. 13, 187 (2018).

    PubMed  PubMed Central  Article  Google Scholar 

  73. Aaron, R. K. et al. Perfusion abnormalities in subchondral bone associated with marrow edema, osteoarthritis, and avascular necrosis. Ann. N. Y. Acad. Sci. 1117, 124–137 (2007).

    PubMed  Article  Google Scholar 

  74. Lip, G. Y. H. & Coca, A. On behalf of the Task Force. Hypertension and cardiac arrhythmias. Eur. Heart J. 38, 223–225 (2017).

    PubMed  Article  Google Scholar 

  75. Aaron, R., Racine, J., Voisinet, A., Evangelista, P. & Dyke, J. Subchondral bone circulation in osteoarthritis of the human knee. Osteoarthritis Cartilage 26, 940–944 (2018).

    CAS  PubMed  Article  Google Scholar 

  76. Arnoldi, C. C., Linderholm, H. & Müssbichler, H. Venous engorgement and intraosseous hypertension in osteoarthritis of the hip. J. Bone Joint Surg. Br. 54, 409–421 (1972).

    CAS  PubMed  Article  Google Scholar 

  77. Chan, P. M. B., Wen, C., Yang, W. C., Yan, C. & Chiu, K. Is subchondral bone cyst formation in non-load-bearing region of osteoarthritic knee a vascular problem? Med. Hypotheses 109, 80–83 (2017).

    CAS  PubMed  Article  Google Scholar 

  78. Liu, Z. et al. Photoacoustic imaging of synovial tissue hypoxia in experimental post-traumatic osteoarthritis. Prog. Biophy. Mol. Biol. 148, 12–20 (2019).

    Article  Google Scholar 

  79. Lee, J. H. et al. Subchondral fluid dynamics in a model of osteoarthritis: use of dynamic contrast-enhanced magnetic resonance imaging. Osteoarthritis Cartilage 17, 1350–1355 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  80. Richman, A. I., Su, E. Y. & Ho, G. Jr. Reciprocal relationship of synovial fluid volume and oxygen tension. Arthritis Rheum. 24, 701–705 (1981).

    CAS  PubMed  Article  Google Scholar 

  81. Falchuk, K., Goetzl, E. & Kulka, J. Respiratory gases of synovial fluids: an approach to synovial tissue circulatory-metabolic imbalance in rheumatoid arthritis. Am. J. Med. 49, 223–231 (1970).

    CAS  PubMed  Article  Google Scholar 

  82. Geborek, P., Forslind, K. & Wollheim, F. Direct assessment of synovial blood flow and its relation to induced hydrostatic pressure changes. Ann. Rheum. Dis. 48, 281–286 (1989).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  83. Kiaer, T., Grønlund, J. & Sørensen, K. Subchondral pO2, pCO2, pressure, pH, and lactate in human osteoarthritis of the hip. Clin. Orthop. Relat. Res. 229, 149–155 (1988).

    Google Scholar 

  84. Kiær, T., Dahl, B. & Lausten, G. S. The relationship between inert gas wash-out and radioactive tracer microspheres in measurement of bone blood flow: effect of decreased arterial supply and venous congestion on bone blood flow in an animal model. J. Orthop. Res. 11, 28–35 (1993).

    PubMed  Article  Google Scholar 

  85. James, J. & Steijn-Myagkaya, G. Death of osteocytes. Electron microscopy after in vitro ischaemia. J. Bone Joint Surg. Br. 68, 620–624 (1986).

    CAS  PubMed  Article  Google Scholar 

  86. Catto, M. Ischaemia of bone. J. Clin. Pathol. Suppl. 11, 78–93 (1977).

    CAS  Article  Google Scholar 

  87. Archer, C. W. & Francis-West, P. The chondrocyte. Int. J. Biochem. Cell Biol. 35, 401–404 (2003).

    CAS  PubMed  Article  Google Scholar 

  88. Rosa, S. C. et al. Role of glucose as a modulator of anabolic and catabolic gene expression in normal and osteoarthritic human chondrocytes. J. Cell. Biochem. 112, 2813–2824 (2011).

    CAS  PubMed  Article  Google Scholar 

  89. Mobasheri, A. et al. Glucose transport and metabolism in chondrocytes: a key to understanding chondrogenesis, skeletal development and cartilage degradation in osteoarthritis. Histol. Histopathol. 17, 1239–1267 (2002).

    CAS  PubMed  Google Scholar 

  90. Peansukmanee, S. et al. Effects of hypoxia on glucose transport in primary equine chondrocytes in vitro and evidence of reduced GLUT1 gene expression in pathologic cartilage in vivo. J. Orthop. Res. 27, 529–535 (2009).

    CAS  PubMed  Article  Google Scholar 

  91. Mobasheri, A. et al. The role of metabolism in the pathogenesis of osteoarthritis. Nat. Rev. Rheumatol. 13, 302–311 (2017).

    CAS  PubMed  Article  Google Scholar 

  92. Martín-Vasallo, P. et al. Sodium transport systems in human chondrocytes II. Expression of ENaC, Na+/K+/2CI-cotransporter and Na+/H+ exchangers in healthy and arthritic chondrocytes. Histol. Histopathol. 14, 1023–1031 (1999).

    PubMed  Google Scholar 

  93. Tomlinson, R. E. & Silva, M. J. Skeletal blood flow in bone repair and maintenance. Bone Res. 1, 311–322 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  94. Wittkowske, C., Reilly, G. C., Lacroix, D. & Perrault, C. M. In vitro bone cell models: impact of fluid shear stress on bone formation. Front. Bioeng. Biotechnol. 4, 87 (2016).

    PubMed  PubMed Central  Article  Google Scholar 

  95. Liu, L., Yuan, W. & Wang, J. Mechanisms for osteogenic differentiation of human mesenchymal stem cells induced by fluid shear stress. Biomech. Model. Mechanobiol. 9, 659–670 (2010).

    PubMed  Article  Google Scholar 

  96. Rangaswami, H. et al. Type II cGMP-dependent protein kinase mediates osteoblast mechanotransduction. J. Biol. Chem. 284, 14796–14808 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  97. Van Beuningen, H., Glansbeek, H., Van Der Kraan, P. & Van den Berg, W. Osteoarthritis-like changes in the murine knee joint resulting from intra-articular transforming growth factor-β injections. Osteoarthritis Cartilage 8, 25–33 (2000).

    PubMed  Article  Google Scholar 

  98. Ridnour, L. A. et al. Nitric oxide regulates matrix metalloproteinase-9 activity by guanylyl-cyclase-dependent and -independent pathways. Proc. Natl Acad. Sci. USA 104, 16898–16903 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. Jaiprakash, A. et al. Phenotypic characterization of osteoarthritic osteocytes from the sclerotic zones: a possible pathological role in subchondral bone sclerosis. Int. J. Biol. Sci. 8, 406–417 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  100. Kennedy, O. D., Laudier, D. M., Majeska, R. J., Sun, H. B. & Schaffler, M. B. Osteocyte apoptosis is required for production of osteoclastogenic signals following bone fatigue in vivo. Bone 64, 132–137 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  101. Cheung, W. Y. et al. Pannexin-1 and P2X7-receptor are required for apoptotic osteocytes in fatigued bone to trigger RANKL production in neighboring bystander osteocytes. J. Bone Miner. Res. 31, 890–899 (2016).

    CAS  PubMed  Article  Google Scholar 

  102. Bertuglia, A. et al. Osteoclasts are recruited to the subchondral bone in naturally occurring post-traumatic equine carpal osteoarthritis and may contribute to cartilage degradation. Osteoarthritis Cartilage 24, 555–566 (2016).

    CAS  PubMed  Article  Google Scholar 

  103. Zhu, J. et al. HIF-1α facilitates osteocyte-mediated osteoclastogenesis by activating JAK2/STAT3 pathway in vitro. J. Cell. Physiol. 234, 21182–21192 (2019).

    CAS  PubMed  Article  Google Scholar 

  104. Zhu, S. et al. Subchondral bone osteoclasts induce sensory innervation and osteoarthritis pain. J. Clin. Invest. 129, 1076–1093 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  105. Mun, S. H., Park, P. S. U. & Park-Min, K.-H. The M-CSF receptor in osteoclasts and beyond. Exp. Mol. Med. 52, 1239–1254 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  106. Felix, R., Cecchini, M. & Fleisch, H. Macrophage colony stimulating factor restores in vivo bone resorption in the op/op osteopetrotic mouse. Endocrinology 127, 2592–2594 (1990).

    CAS  PubMed  Article  Google Scholar 

  107. Orcel, P., Feuga, M., Bielakoff, J. & De Vernejoul, M. Local bone injections of LPS and M-CSF increase bone resorption by different pathways in vivo in rats. Am. J. Physiol. Endocrinol. Metab. 264, E391–E397 (1993).

    CAS  Article  Google Scholar 

  108. Tiyasatkulkovit, W. et al. Impairment of bone microstructure and upregulation of osteoclastogenic markers in spontaneously hypertensive rats. Sci. Rep. 9, 12293 (2019).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  109. Chamarthi, B. et al. Inflammation and hypertension: the interplay of interleukin-6, dietary sodium, and the renin–angiotensin system in humans. Am. J. Hypertens. 24, 1143–1148 (2011).

    CAS  PubMed  Article  Google Scholar 

  110. Zhang, W. et al. Interleukin 6 underlies angiotensin II-induced hypertension and chronic renal damage. Hypertension 59, 136–144 (2012).

    CAS  PubMed  Article  Google Scholar 

  111. Kudo, O. et al. Interleukin-6 and interleukin-11 support human osteoclast formation by a RANKL-independent mechanism. Bone 32, 1–7 (2003).

    CAS  PubMed  Article  Google Scholar 

  112. Andreev, D. et al. Osteocyte necrosis triggers osteoclast-mediated bone loss through macrophage-inducible C-type lectin. J. Clin. Invest. 130, 4811–4830 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. Millerand, M., Berenbaum, F. & Jacques, C. Danger signals and inflammaging in osteoarthritis. Clin. Exp. Rheumatol. 37, 48–56 (2019).

    PubMed  Google Scholar 

  114. Yao, J. et al. Deterioration of stress distribution due to tunnel creation in single-bundle and double-bundle anterior cruciate ligament reconstructions. Ann. Biomed. Eng. 40, 1554–1567 (2012).

    PubMed  Article  Google Scholar 

  115. Yao, J. et al. Effect of tibial drill-guide angle on the mechanical environment at bone tunnel aperture after anatomic single-bundle anterior cruciate ligament reconstruction. Int. Orthop. 38, 973–981 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  116. Shabestari, M., Vik, J., Reseland, J. & Eriksen, E. Bone marrow lesions in hip osteoarthritis are characterized by increased bone turnover and enhanced angiogenesis. Osteoarthritis Cartilage 24, 1745–1752 (2016).

    CAS  PubMed  Article  Google Scholar 

  117. Muratovic, D. et al. Bone matrix microdamage and vascular changes characterize bone marrow lesions in the subchondral bone of knee osteoarthritis. Bone 108, 193–201 (2018).

    CAS  PubMed  Article  Google Scholar 

  118. Hunter, D. J. et al. Increase in bone marrow lesions associated with cartilage loss: a longitudinal magnetic resonance imaging study of knee osteoarthritis. Arthritis Rheum. 54, 1529–1535 (2006).

    PubMed  Article  Google Scholar 

  119. Felson, D. T. et al. The association of bone marrow lesions with pain in knee osteoarthritis. Ann. Intern. Med. 134, 541–549 (2001).

    CAS  PubMed  Article  Google Scholar 

  120. Link, T. M. et al. Osteoarthritis: MR imaging findings in different stages of disease and correlation with clinical findings. Radiology 226, 373–381 (2003).

    PubMed  Article  Google Scholar 

  121. Kornaat, P. R. et al. Osteoarthritis of the knee: association between clinical features and MR imaging findings. Radiology 239, 811–817 (2006).

    PubMed  Article  Google Scholar 

  122. Raynauld, J. P. et al. Correlation between bone lesion changes and cartilage volume loss in patients with osteoarthritis of the knee as assessed by quantitative magnetic resonance imaging over a 24-month period. Ann. Rheum. Dis. 67, 683–688 (2008).

    PubMed  Article  Google Scholar 

  123. McErlain, D. D. et al. An in vivo investigation of the initiation and progression of subchondral cysts in a rodent model of secondary osteoarthritis. Arthritis Res. Ther. 14, R26 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  124. Winet, H., Hsieh, A. & Bao, J. Approaches to study of ischemia in bone. J. Biomed. Mater. Res. 43, 410–421 (1998).

    CAS  PubMed  Article  Google Scholar 

  125. Intema, F. et al. In early OA, thinning of the subchondral plate is directly related to cartilage damage: results from a canine ACLT-meniscectomy model. Osteoarthritis Cartilage 18, 691–698 (2010).

    CAS  PubMed  Article  Google Scholar 

  126. Wagegg, M. et al. Hypoxia promotes osteogenesis but suppresses adipogenesis of human mesenchymal stromal cells in a hypoxia-inducible factor-1 dependent manner. PloS ONE 7, e46483 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. Lajeunesse, D. The role of bone in the treatment of osteoarthritis. Osteoarthritis Cartilage 12, 34–38 (2004).

    Article  Google Scholar 

  128. Chan, T. F. et al. Elevated Dickkopf-2 levels contribute to the abnormal phenotype of human osteoarthritic osteoblasts. J. Bone Miner. Res. 26, 1399–1410 (2011).

    CAS  PubMed  Article  Google Scholar 

  129. Hwang, J. et al. Increased hydraulic conductance of human articular cartilage and subchondral bone plate with progression of osteoarthritis. Arthritis Rheum. 58, 3831–3842 (2008).

    PubMed  PubMed Central  Article  Google Scholar 

  130. Pan, J. et al. Elevated cross-talk between subchondral bone and cartilage in osteoarthritic joints. Bone 51, 212–217 (2012).

    PubMed  Article  Google Scholar 

  131. Westacott, C. I., Webb, G. R., Warnock, M. G., Sims, J. V. & Elson, C. J. Alteration of cartilage metabolism by cells from osteoarthritic bone. Arthritis Rheum. 40, 1282–1291 (1997).

    CAS  PubMed  Article  Google Scholar 

  132. Priam, S. et al. Identification of soluble 14-3-3 as a novel subchondral bone mediator involved in cartilage degradation in osteoarthritis. Arthritis Rheum. 65, 1831–1842 (2013).

    CAS  PubMed  Article  Google Scholar 

  133. Weber, A., Chan, P. M. B. & Wen, C. Do immune cells lead the way in subchondral bone disturbance in osteoarthritis? Prog. Biophys. Mol. Biol. 148, 21–31 (2019).

    CAS  PubMed  Article  Google Scholar 

  134. Goldring, S. R. & Goldring, M. B. Changes in the osteochondral unit during osteoarthritis: structure, function and cartilage–bone crosstalk. Nat. Rev. Rheumatol. 12, 632–644 (2016).

    PubMed  Article  Google Scholar 

  135. Fernandez-Madrid, F., Karvonen, R. L., Teitge, R. A., Miller, P. R. & Negendank, W. G. MR features of osteoarthritis of the knee. Magn. Reson. Imaging 12, 703–709 (1994).

    CAS  PubMed  Article  Google Scholar 

  136. Hill, C. L. et al. Knee effusions, popliteal cysts, and synovial thickening: association with knee pain in osteoarthritis. J. Rheumatol. 28, 1330–1337 (2001).

    CAS  PubMed  Google Scholar 

  137. Arnoldi, C. C., Reimann, I. & Bretlau, P. The synovial membrane in human coxathrosis: light and electron microscopic studies. Clin. Orthop. Relat. Res. 148, 213–220 (1980).

    Google Scholar 

  138. Reimann, I., Arnoldi, C. C. & Nielsen, O. Permeability of synovial membrane to plasma proteins in human coxarthrosis: relation to molecular size and histologic changes. Clin. Orthop. Relat. Res. 147, 296–300 (1980).

    CAS  Google Scholar 

  139. Mobasheri, A., Moskaluk, C. A., Marples, D. & Shakibaei, M. Expression of aquaporin 1 (AQP1) in human synovitis. Ann. Anat. 192, 116–121 (2010).

    PubMed  Article  Google Scholar 

  140. Toussaint, J. et al. Chronic hypertension increases aortic endothelial hydraulic conductivity by upregulating endothelial aquaporin-1 expression. Am. J. Physiol. Heart Circ. Physiol. 313, H1063–H1073 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  141. Sattar, A., Kumar, P. & Kumar, S. Rheumatoid-and osteo-arthritis: quantitation of ultrastructural features of capillary endothelial cells. J. Pathol. 148, 45–53 (1986).

    CAS  PubMed  Article  Google Scholar 

  142. Rondaij, M. G., Bierings, R., Kragt, A., van Mourik, J. A. & Voorberg, J. Dynamics and plasticity of Weibel-Palade bodies in endothelial cells. Arterioscler. Thromb. Vasc. Biol. 26, 1002–1007 (2006).

    CAS  PubMed  Article  Google Scholar 

  143. Schillemans, M. et al. Weibel-Palade body localized syntaxin-3 modulates Von Willebrand factor secretion from endothelial cells. Arterioscler. Thromb. Vasc. Biol. 38, 1549–1561 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  144. Ozaka, T., Doi, Y., Kayashima, K. & Fujimoto, S. Weibel-Palade bodies as a storage site of calcitonin gene-related peptide and endothelin-1 in blood vessels of the rat carotid body. Anat. Record 247, 388–394 (1997).

    CAS  Article  Google Scholar 

  145. Xiong, Y. et al. Hypertensive stretch regulates endothelial exocytosis of Weibel-Palade bodies through VEGF receptor 2 signaling pathways. Cell Res. 23, 820–834 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  146. Pinsky, D. J. et al. Hypoxia-induced exocytosis of endothelial cell Weibel-Palade bodies. A mechanism for rapid neutrophil recruitment after cardiac preservation. J. Clin. Invest. 97, 493–500 (1996).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  147. Kudo, H. et al. Enhanced expression of endothelin-1 and endothelin-converting enzyme-1 in acute hypoxic rat aorta. Histol. Histopathol. 17, 97–105 (2002).

    PubMed  Google Scholar 

  148. Doi, Y. et al. Histamine release from Weibel-Palade bodies of toad aortas induced by endothelin-1 and sarafotoxin-S6b. Anat. Rec. 242, 374–382 (1995).

    CAS  PubMed  Article  Google Scholar 

  149. Nahir, A., Hoffman, A., Lorber, M. & Keiser, H. Presence of immunoreactive endothelin in synovial fluid: analysis of 22 cases. J. Rheumatol. 18, 678–680 (1991).

    CAS  PubMed  Google Scholar 

  150. Wharton, J. et al. Autoradiographic localization and analysis of endothelin-1 binding sites in human synovial tissue. Arthritis Rheum. 35, 894–899 (1992).

    CAS  PubMed  Article  Google Scholar 

  151. Olmos, G. et al. Hyperphosphatemia induces senescence in human endothelial cells by increasing endothelin-1 production. Aging Cell 16, 1300–1312 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  152. Chopra, S., Baby, C. & Jacob, J. J. Neuro-endocrine regulation of blood pressure. Indian J. Endocrinol. Metab. 15 (Suppl. 4), S281–S288 (2011).

    PubMed  PubMed Central  Google Scholar 

  153. Schiffrin, E. L. Vascular endothelin in hypertension. Vasc. Pharmacol. 43, 19–29 (2005).

    CAS  Article  Google Scholar 

  154. Ng, L. F. et al. WNT signaling in disease. Cells 8, 826 (2019).

    CAS  PubMed Central  Article  Google Scholar 

  155. Catt, K. et al. Angiotensin II blood-levels in human hypertension. Lancet 297, 459–464 (1971).

    Article  Google Scholar 

  156. Paul, M., Poyan Mehr, A. & Kreutz, R. Physiology of local renin-angiotensin systems. Physiol. Rev. 86, 747–803 (2006).

    CAS  PubMed  Article  Google Scholar 

  157. Kawakami, Y. et al. Expression of angiotensin II receptor-1 in human articular chondrocytes. Arthritis 2012, 648537 (2012).

    PubMed  PubMed Central  Article  Google Scholar 

  158. Tsukamoto, I. et al. Expressions of local renin-angiotensin system components in chondrocytes. Eur. J. Histochem. 58, 2387 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  159. Wu, Y. et al. Differential expression of renin-angiotensin system-related components in patients with rheumatoid arthritis and osteoarthritis. Am. J. Med. Sci. 359, 17–26 (2020).

    PubMed  Article  Google Scholar 

  160. Tang, Y., Hu, X. & Lu, X. Captopril, an angiotensin-converting enzyme inhibitor, possesses chondroprotective efficacy in a rat model of osteoarthritis through suppression local renin-angiotensin system. Int. J. Clin. Exp. Med. 8, 12584 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  161. Tsukamoto, I. et al. Activating types 1 and 2 angiotensin II receptors modulate the hypertrophic differentiation of chondrocytes. FEBS Open Bio. 3, 279–284 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  162. Kawahata, H. et al. Continuous infusion of angiotensin II modulates hypertrophic differentiation and apoptosis of chondrocytes in cartilage formation in a fracture model mouse. Hypertens. Res. 38, 382–393 (2015).

    CAS  PubMed  Article  Google Scholar 

  163. Osako, M. K. et al. Cross-talk of receptor activator of nuclear factor-κB ligand signaling with renin–angiotensin system in vascular calcification. Arterioscler. Thromb. Vasc. Biol. 33, 1287–1296 (2013).

    CAS  PubMed  Article  Google Scholar 

  164. Rattazzi, M., Bertacco, E., Puato, M., Faggin, E. & Pauletto, P. Hypertension and vascular calcification: a vicious cycle? J. Hypertens. 30, 1885–1893 (2012).

    CAS  PubMed  Article  Google Scholar 

  165. Shimizu, H. et al. Angiotensin II accelerates osteoporosis by activating osteoclasts. FASEB J. 22, 2465–2475 (2008).

    CAS  PubMed  Article  Google Scholar 

  166. Asaba, Y. et al. Activation of renin-angiotensin system induces osteoporosis independently of hypertension. J. Bone Miner. Res. 24, 241–250 (2009).

    CAS  PubMed  Article  Google Scholar 

  167. Touyz, R. M. & Schiffrin, E. L. Role of endothelin in human hypertension. Can. J. Physiol. Pharmacol. 81, 533–541 (2003).

    CAS  PubMed  Article  Google Scholar 

  168. Barton, M., Shaw, S., Moreau, P. & Lüscher, T. F. Angiotensin II increases vascular and renal endothelin-1 and functional endothelin converting enzyme activityin vivo: role of ETA receptors for endothelin regulation. Biochem. Biophys. Res. Commun. 238, 861–865 (1997).

    CAS  PubMed  Article  Google Scholar 

  169. Böhm, F. & Pernow, J. The importance of endothelin-1 for vascular dysfunction in cardiovascular disease. Cardiovasc. Res. 76, 8–18 (2007).

    PubMed  Article  CAS  Google Scholar 

  170. Zhao, Z., Li, E., Cao, Q., Sun, J. & Ma, B. Endothelin-1 concentrations are correlated with the severity of knee osteoarthritis. J. Invest. Med. 64, 872–874 (2016).

    Article  Google Scholar 

  171. Roy-Beaudry, M. et al. Endothelin 1 promotes osteoarthritic cartilage degradation via matrix metalloprotease 1 and matrix metalloprotease 13 induction. Arthritis Rheum. 48, 2855–2864 (2003).

    CAS  PubMed  Article  Google Scholar 

  172. Manacu, C. A. et al. Endothelin-1 in osteoarthritic chondrocytes triggers nitric oxide production and upregulates collagenase production. Arthritis Res. Ther. 7, R324 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  173. Kaufman, G. N., Zaouter, C., Valteau, B., Sirois, P. & Moldovan, F. Nociceptive tolerance is improved by bradykinin receptor B1 antagonism and joint morphology is protected by both endothelin type A and bradykinin receptor B1 antagonism in a surgical model of osteoarthritis. Arthritis Res. Ther. 13, R76 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  174. Vallee, A., Levy, B. L. & Blacher, J. Interplay between the renin-angiotensin system, the canonical WNT/β-catenin pathway and PPARγ in hypertension. Curr. Hypertens. Rep. 20, 62 (2018).

    PubMed  Article  CAS  Google Scholar 

  175. Kim, S.-J. et al. β-Catenin regulates expression of cyclooxygenase-2 in articular chondrocytes. Biochem. Biophys. Res. Commun. 296, 221–226 (2002).

    CAS  PubMed  Article  Google Scholar 

  176. Wain, L. V. et al. Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure. Nat. Genet. 43, 1005–1011 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  177. Kuipers, A. L. et al. Wnt pathway gene expression is associated with arterial stiffness. J. Am. Heart Assoc. 9, e014170 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  178. Sarzani, R. et al. Carotid artery atherosclerosis in hypertensive patients with a functional LDL receptor-related protein 6 gene variant. Nutr. Metab. Cardiovasc. Dis. 21, 150–156 (2011).

    CAS  PubMed  Article  Google Scholar 

  179. Zhou, L. et al. Multiple genes of the renin-angiotensin system are novel targets of Wnt/β-catenin signaling. J. Am. Soc. Nephrol. 26, 107–120 (2015).

    CAS  PubMed  Article  Google Scholar 

  180. Sumida, T. et al. Complement C1q-induced activation of β-catenin signalling causes hypertensive arterial remodelling. Nat. Commun. 6, 6241 (2015).

    CAS  PubMed  Article  Google Scholar 

  181. Cuevas, C. A., Gonzalez, A. A., Inestrosa, N. C., Vio, C. P. & Prieto, M. C. Angiotensin II increases fibronectin and collagen I through the β-catenin-dependent signaling in mouse collecting duct cells. Am. J. Physiol. Renal Physiol. 308, F358–F365 (2015).

    CAS  PubMed  Article  Google Scholar 

  182. Corr, M. Wnt–β-catenin signaling in the pathogenesis of osteoarthritis. Nat. Clin. Pract. Rheumatol. 4, 550–556 (2008).

    CAS  PubMed  Article  Google Scholar 

  183. Day, T. F., Guo, X., Garrett-Beal, L. & Yang, Y. Wnt/β-catenin signaling in mesenchymal progenitors controls osteoblast and chondrocyte differentiation during vertebrate skeletogenesis. Dev. Cell 8, 739–750 (2005).

    CAS  PubMed  Article  Google Scholar 

  184. Hopwood, B., Tsykin, A., Findlay, D. M. & Fazzalari, N. L. Microarray gene expression profiling of osteoarthritic bone suggests altered bone remodelling, WNT and transforming growth factor-β/bone morphogenic protein signalling. Arthritis Res. Ther. 9, R100 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  185. Dell’Accio, F., De Bari, C., Eltawil, N. M., Vanhummelen, P. & Pitzalis, C. Identification of the molecular response of articular cartilage to injury, by microarray screening: Wnt-16 expression and signaling after injury and in osteoarthritis. Arthritis Rheum. 58, 1410–1421 (2008).

    PubMed  Article  CAS  Google Scholar 

  186. Barker, N. in Wnt Signaling Volume 1: Pathway Methods and Mammalian Models (ed Vincan, E.) 5–15 (Springer, 2008).

  187. Lane, N. E., Nevitt, M. C., Lui, L. Y., De Leon, P. & Corr, M. Wnt signaling antagonists are potential prognostic biomarkers for the progression of radiographic hip osteoarthritis in elderly Caucasian women. Arthritis Rheum. 56, 3319–3325 (2007).

    CAS  PubMed  Article  Google Scholar 

  188. Min, J. et al. Association of the Frizzled-related protein gene with symptomatic osteoarthritis at multiple sites. Arthritis Rheum. 52, 1077–1080 (2005).

    CAS  PubMed  Article  Google Scholar 

  189. Valdes, A. M. et al. Sex and ethnic differences in the association of ASPN, CALM1, COL2A1, COMP, and FRZB with genetic susceptibility to osteoarthritis of the knee. Arthritis Rheum. 56, 137–146 (2007).

    CAS  PubMed  Article  Google Scholar 

  190. Clines, G. A. et al. Dickkopf homolog 1 mediates endothelin-1-stimulated new bone formation. Mol. Endocrinol. 21, 486–498 (2007).

    CAS  PubMed  Article  Google Scholar 

  191. Zhang, Y. et al. Renin inhibitor aliskiren exerts beneficial effect on trabecular bone by regulating skeletal renin-angiotensin system and kallikrein-kinin system in ovariectomized mice. Osteoporos. Int. 27, 1083–1092 (2016).

    CAS  PubMed  Article  Google Scholar 

  192. Gu, S.-S. et al. Involvement of the skeletal renin-angiotensin system in age-related osteoporosis of ageing mice. Biosci. Biotechnol. Biochem. 76, 1367–1371 (2012).

    CAS  PubMed  Article  Google Scholar 

  193. Price, A. et al. Angiotensin II type 1 receptor as a novel therapeutic target in rheumatoid arthritis: in vivo analyses in rodent models of arthritis and ex vivo analyses in human inflammatory synovitis. Arthritis Rheum. 56, 441–447 (2007).

    CAS  PubMed  Article  Google Scholar 

  194. Cobankara, V. et al. Renin and angiotensin-converting enzyme (ACE) as active components of the local synovial renin-angiotensin system in rheumatoid arthritis. Rheumatol. Int. 25, 285–291 (2005).

    CAS  PubMed  Article  Google Scholar 

  195. Yan, K. & Shen, Y. Aliskiren has chondroprotective efficacy in a rat model of osteoarthritis through suppression of the local renin-angiotensin system. Mol. Med. Rep. 16, 3965–3973 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  196. Chan, P. et al. Role of systemic hypertension in cell senescence and subchondral bone disturbance of knee joint [abstract]. Osteoarthritis Cartilage 26, S118 (2018).

    Article  Google Scholar 

  197. Silveira, K. D. et al. Mechanisms of the anti-inflammatory actions of the angiotensin type 1 receptor antagonist losartan in experimental models of arthritis. Peptides 46, 53–63 (2013).

    CAS  PubMed  Article  Google Scholar 

  198. Kwok, T. et al. Does the use of ACE inhibitors or angiotensin receptor blockers affect bone loss in older men? Osteoporos. Int. 23, 2159–2167 (2012).

    CAS  PubMed  Article  Google Scholar 

  199. Wen, C., Yan, C. & Chiu, K. Development of osteoarthritis-like changes in transgenic endothelin-1 overexpressed mice [abstract]. Osteoarthritis Cartilage 22, S363 (2014).

    Article  Google Scholar 

  200. Zhao, W., Leung, V., Chiu, K., Chung, S. & Lu, W. Role of endothelin-1 in endochondral ossification and osteoarthritis [abstract]. Osteoarthritis Cartilage 24, S51–S52 (2016).

    Article  Google Scholar 

  201. Au, M., Liu, Z., Rong, L., Zheng, Y. & Wen, C. Endothelin-1 induces chondrocyte senescence and cartilage damage via endothelin receptor type B in a post-traumatic osteoarthritis mouse model. Osteoarthritis Cartilage 28, 1559–1571 (2020).

    CAS  PubMed  Article  Google Scholar 

  202. Hoeppner, L. H., Secreto, F. J. & Westendorf, J. J. Wnt signaling as a therapeutic target for bone diseases. Expert Opin. Therap. Targets 13, 485–496 (2009).

    CAS  Article  Google Scholar 

  203. Wang, Y., Fan, X., Xing, L. & Tian, F. Wnt signaling: a promising target for osteoarthritis therapy. Cell Commun. Signal. 17, 97 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  204. Deshmukh, V. et al. A small-molecule inhibitor of the Wnt pathway (SM04690) as a potential disease modifying agent for the treatment of osteoarthritis of the knee. Osteoarthritis Cartilage 26, 18–27 (2018).

    CAS  PubMed  Article  Google Scholar 

  205. Takamatsu, A. et al. Verapamil protects against cartilage degradation in osteoarthritis by inhibiting Wnt/β-catenin signaling. PLoS ONE 9, e92699 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  206. Ramsay, L. E., Silas, J. H. & Freestone, S. Diuretic treatment of resistant hypertension. Br. Med. J. 281, 1101–1103 (1980).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  207. Elsaman, A. M., Radwan, A. R., Mohammed, W. I. & Ohrndorf, S. Low-dose spironolactone: treatment for osteoarthritis-related knee effusion. A prospective clinical and sonographic-based study. J. Rheumatol. 43, 1114–1120 (2016).

    CAS  PubMed  Article  Google Scholar 

  208. Youcef, G. et al. Preventive and chronic mineralocorticoid receptor antagonism is highly beneficial in obese SHHF rats. Br. J. Pharmacol. 173, 1805–1819 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  209. Deng, C. et al. Eplerenone treatment alleviates the development of joint lesions in a new rat model of spontaneous metabolic-associated osteoarthritis. Ann. Rheum. Dis. 77, 315–316 (2018).

    CAS  PubMed  Article  Google Scholar 

  210. Yuan, F.-L. et al. Inhibition of acid-sensing ion channels in articular chondrocytes by amiloride attenuates articular cartilage destruction in rats with adjuvant arthritis. Inflamm. Res. 59, 939–947 (2010).

    CAS  PubMed  Article  Google Scholar 

  211. Izumi, M., Ikeuchi, M., Ji, Q. & Tani, T. Local ASIC3 modulates pain and disease progression in a rat model of osteoarthritis. J. Biomed. Sci. 19, 77 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  212. TenBroek, E. M., Yunker, L., Nies, M. F. & Bendele, A. M. Randomized controlled studies on the efficacy of antiarthritic agents in inhibiting cartilage degeneration and pain associated with progression of osteoarthritis in the rat. Arthritis Res. Ther. 18, 24 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  213. Reuben, S. S. & Sklar, J. Intravenous regional anesthesia with clonidine in the management of complex regional pain syndrome of the knee. J. Clin. Anesth. 14, 87–91 (2002).

    CAS  PubMed  Article  Google Scholar 

  214. Valdes, A. M. et al. Association of beta-blocker use with less prevalent joint pain and lower opioid requirement in people with osteoarthritis. Arthritis Care Res. 69, 1076–1081 (2017).

    CAS  Article  Google Scholar 

  215. Zhou, L., Kwoh, C., Ran, D., Ashbeck, E. & Lo-Ciganic, W.-H. Lack of evidence that beta blocker use reduces knee pain, areas of joint pain, or analgesic use among individuals with symptomatic knee osteoarthritis. Osteoarthritis Cartilage 28, 53–61 (2020).

    CAS  PubMed  Article  Google Scholar 

  216. Garlichs, C., Zhang, H., Mügge, A. & Daniel, W. Beta-blockers reduce the release and synthesis of endothelin-1 in human endothelial cells. Eur. J. Clin. Invest. 29, 12–16 (1999).

    CAS  PubMed  Article  Google Scholar 

  217. Uzieliene, I. et al. The antihypertensive drug nifedipine modulates the metabolism of chondrocytes and human bone marrow-derived mesenchymal stem cells. Front. Endocrinol. 10, 756 (2019).

    Article  Google Scholar 

  218. Abramson, S. B. Osteoarthritis and nitric oxide. Osteoarthritis Cartilage 16 (Suppl. 2), S15–S20 (2008).

    Article  Google Scholar 

  219. Raisi-Estabragh, Z. et al. Poor bone quality is associated with greater arterial stiffness: insights from the UK Biobank. J. Bone Miner. Res. 36, 90–99 (2021).

    PubMed  Article  Google Scholar 

  220. Saavedra, J. M. Naloxone reversible decrease in pain sensitivity in young and adult spontaneously hypertensive rats. Brain Res. 209, 245–249 (1981).

    CAS  PubMed  Article  Google Scholar 

  221. Lewis, S. J., Meller, S. T., Brody, M. J. & Gebhart, G. Reduced nociceptive effects of intravenous serotonin (5-HT) in the spontaneously hypertensive rat. Clin. Exp. Hypertens. A 13, 849–857 (1991).

    CAS  PubMed  Google Scholar 

  222. Ring, C. et al. Effects of naltrexone on electrocutaneous pain in patients with hypertension compared to normotensive individuals. Biol. Psychol. 77, 191–196 (2008).

    PubMed  Article  Google Scholar 

  223. Sheps, D. S. et al. Relation between systemic hypertension and pain perception. Am. J. Cardiol. 70, F3–F5 (1992).

    Article  Google Scholar 

  224. Bruehl, S., Chung, O. Y., Ward, P., Johnson, B. & McCubbin, J. A. The relationship between resting blood pressure and acute pain sensitivity in healthy normotensives and chronic back pain sufferers: the effects of opioid blockade. Pain 100, 191–201 (2002).

    CAS  PubMed  Article  Google Scholar 

  225. Bruehl, S., Burns, J. W. & McCubbin, J. A. Altered cardiovascular/pain regulatory relationships in chronic pain. Int. J. Behav. Med. 5, 63–75 (1998).

    CAS  PubMed  Article  Google Scholar 

  226. Bagge, E., Bjelle, A., Eden, S. & Svanborg, A. Factors associated with radiographic osteoarthritis: results from the population study 70-year-old people in Göteborg. J. Rheumatol. 18, 1218–1222 (1991).

    CAS  PubMed  Google Scholar 

  227. Hart, D. J., Doyle, D. V. & Spector, T. D. Association between metabolic factors and knee osteoarthritis in women: The Chingford study. J. Rheumatol. 22, 1118–1123 (1995).

    CAS  PubMed  Google Scholar 

  228. Sowers, M. et al. Association of bone mineral density and sex hormone levels with osteoarthritis of the hand and knee in premenopausal women. Am. J. Epidemiol. 143, 38–47 (1996).

    CAS  PubMed  Article  Google Scholar 

  229. Kim, I. et al. The prevalence of knee osteoarthritis in elderly community residents in Korea. J. Korean Med. Sci. 25, 293 (2010).

    PubMed  PubMed Central  Article  Google Scholar 

  230. Reid, J. L. et al. Obesity and other cardiovascular disease risk factors and their association with osteoarthritis in Southern California American Indians, 2002-2006. Ethn. Dis. 20, 416 (2010).

    PubMed  Google Scholar 

  231. Inoue, R. et al. Medical problems and risk factors of metabolic syndrome among radiographic knee osteoarthritis patients in the Japanese general population. J. Orthop. Sci. 16, 704–709 (2011).

    PubMed  Article  Google Scholar 

  232. Yoshimura, N. et al. Accumulation of metabolic risk factors such as overweight, hypertension, dyslipidaemia, and impaired glucose tolerance raises the risk of occurrence and progression of knee osteoarthritis: a 3-year follow-up of the ROAD study. Osteoarthritis Cartilage 20, 1217–1226 (2012).

    CAS  PubMed  Article  Google Scholar 

  233. Han, C. D., Yang, I. H., Lee, W. S., Park, Y. J. & Park, K. K. Correlation between metabolic syndrome and knee osteoarthritis: data from the Korean National Health and Nutrition Examination Survey (KNHANES). BMC Public Health 13, 603 (2013).

    PubMed  PubMed Central  Article  Google Scholar 

  234. Shin, D. Association between metabolic syndrome, radiographic knee osteoarthritis, and intensity of knee pain: results of a national survey. J. Clin. Endocrinol. Metab. 99, 3177–3183 (2014).

    CAS  PubMed  Article  Google Scholar 

  235. Liu, Y. et al. Prevalence and associated factors of knee osteoarthritis in a rural Chinese adult population: an epidemiological survey. BMC Public Health 16, 94 (2015).

    Article  Google Scholar 

  236. Li, H., George, D. M., Jaarsma, R. L. & Mao, X. Metabolic syndrome and components exacerbate osteoarthritis symptoms of pain, depression and reduced knee function. Ann. Transl. Med. 4, 133 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  237. Kim, H. S. et al. Association between knee osteoarthritis, cardiovascular risk factors, and the Framingham Risk Score in South Koreans: a cross-sectional study. PLoS ONE 11, e0165325 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  238. Xie, D.-x et al. Association between metabolic syndrome and knee osteoarthritis: a cross-sectional study. BMC Musculoskelet. Disord. 18, 533 (2017).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  239. Yasuda, E. et al. Association between the severity of symptomatic knee osteoarthritis and cumulative metabolic factors. Aging Clin. Exp. Res. 30, 481–488 (2018).

    PubMed  Article  Google Scholar 

  240. Sanchez-Santos, M. T. et al. Association of metabolic syndrome with knee and hand osteoarthritis: a community-based study of women. Semin. Arthritis Rheum. 48, 791–798 (2019).

    CAS  PubMed  Article  Google Scholar 

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Acknowledgements

The work of the authors is supported by the Research Grants Council of Hong Kong Early Career Scheme (PolyU 251008/18M) and General Research Fund (15106120), the PROCORE-France/Hong Kong Joint Research Scheme (F-PolyU504/18), the Health and Medical Research Fund Scheme (#01150087, #15161391 and #16172691), and the Project of Strategic Importance at The Hong Kong Polytechnic University (all grants awarded to C.W.).

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Correspondence to Chunyi Wen.

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Nature Reviews Rheumatology thanks R. Okamoto, A. Mobasheri and J.-Y. Reginster for their contribution to the peer review of this work.

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Glossary

T2 values

Values obtained in MRI scans that provide information about the water content and organization of the collagen structure in cartilage.

Metaphyseal bone

The transition zone between the shaft and head of long bones; it is the location of the growth plate, which elongates and grows during bone development.

Diaphyseal bone

The midsection of long bones, composed of tubular cortical bone on the outside and a hollow bone marrow cavity on the inside.

Areolar tissue

A type of connective tissue with loosely organized fibres that provides space for interstitial fluid to fill the tissue to provide nourishment.

Epiphysis

The ends of long bones that are covered with articular cartilage and join adjacent bones.

Weibel–Palade bodies

Storage granules in endothelial cells that can be released through exocytosis.

Hypokalaemia

A situation of electrolyte imbalance with low potassium in blood serum.

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Ching, K., Houard, X., Berenbaum, F. et al. Hypertension meets osteoarthritis — revisiting the vascular aetiology hypothesis. Nat Rev Rheumatol 17, 533–549 (2021). https://doi.org/10.1038/s41584-021-00650-x

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