Research progress of chondrocyte mechanotransduction mediated by TRPV4 and PIEZOs_Journal of Biomedical Engineering

Authors：

ZHANG Qiang ¹ , Godfred K Tawiah ¹ , ZHANG Yanjun ^1,2 , WEI Xiaochun ² , CHEN Weiyi ¹ ,  ZHANG Quanyou ^1,2

1. College of Biomedical Engineering, Taiyuan University of Technology, Taiyuan 030024, P. R. China;
2. Shanxi Key Laboratory of Bone and Soft Tissue Injury Repair, the Second Hospital of Shanxi Medical University, Shanxi Medical University, Taiyuan 030001, P. R. China;

Corresponding author：

ZHANG Quanyou, Email: zhangquanyou@tyut.edu.cn

Keywords：

Osteoarthritis; Chondrocyte; Matrix microenvironment; Calcium signaling; TRPV4; PIEZOs

DOI：

10.7507/1001-5515.202301029

Video：

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Mechanical signal transduction are crucial for chondrocyte in response to mechanical cues during the growth, development and osteoarthritis (OA) of articular cartilage. Extracellular matrix (ECM) turnover regulates the matrix mechanical microenvironment of chondrocytes. Thus, understanding the mechanotransduction mechanisms during chondrocyte sensing the matrix mechanical microenvironment can develop effective targeted therapy for OA. In recent decades, growing evidences are rapidly advancing our understanding of the mechanical force-dependent cartilage remodeling and injury responses mediated by TRPV4 and PIEZOs. In this review, we highlighted the mechanosensing mechanism mediated by TRPV4 and PIEZOs during chondrocytes sensing mechanical microenvironment of the ECM. Additionally, the latest progress in the regulation of OA by inflammatory signals mediated by TRPV4 and PIEZOs was also introduced. These recent insights provide the potential mechanotheraputic strategies to target these channels and prevent cartilage degeneration associated with OA. This review will shed light on the pathogenesis of articular cartilage, searching clinical targeted therapies, and designing cell-induced biomaterials.

Citation： ZHANG Qiang, Godfred K Tawiah, ZHANG Yanjun, WEI Xiaochun, CHEN Weiyi, ZHANG Quanyou. Research progress of chondrocyte mechanotransduction mediated by TRPV4 and PIEZOs. Journal of Biomedical Engineering, 2023, 40(4): 638-644. doi: 10.7507/1001-5515.202301029 Copy

1.	Han S. Osteoarthritis year in review 2022: biology. Osteoarthr Cartil, 2022, 30(12): 1575-1582.
2.	Ching K, Houard X, Berenbaum F, et al. Hypertension meets osteoarthritis-revisiting the vascular aetiology hypothesis. Nat Rev Rheumatol, 2021, 17(9): 533-549.
3.	Gao W, Hasan H, Anderson D E, et al. The role of mechanically-activated ion channels Piezo1, Piezo2, and TRPV4 in chondrocyte mechanotransduction and mechano-therapeutics for osteoarthritis. Front Cell Dev Biol, 2022: 1002.
4.	Guilak F, Nims R J, Dicks A, et al. Osteoarthritis as a disease of the cartilage pericellular matrix. Matrix Biol, 2018, 71-72: 40-50.
5.	Jiang W, Liu H, Wan R, et al. Mechanisms linking mitochondrial mechanotransduction and chondrocyte biology in the pathogenesis of osteoarthritis. Ageing Res Rev, 2021, 67: 101315.
6.	Hodgkinson T, Kelly D C, Curtin C M, et al. Mechanosignalling in cartilage: an emerging target for the treatment of osteoarthritis. Nat Rev Rheumatol, 2022, 18(2): 67-84.
7.	Zhang M, Meng N, Wang X, et al. TRPV4 and PIEZO channels mediate the mechanosensing of chondrocytes to the biomechanical microenvironment. Membranes, 2022, 12(2): 237.
8.	Martinac B. 2021 Nobel Prize for mechanosensory transduction. Biophys Rev, 2022, 14(1): 15-20.
9.	Corey D P, Hudspeth A J. Ionic basis of the receptor potential in a vertebrate hair cell. Nature, 1979, 281(5733): 675-677.
10.	Phan M N, Leddy H A, Votta B J, et al. Functional characterization of TRPV4 as an osmotically sensitive ion channel in porcine articular chondrocytes. Arthritis Rheum, 2009, 60(10): 3028-3037.
11.	Lee W, Leddy H A, Chen Y, et al. Synergy between Piezo1 and Piezo2 channels confers high-strain mechanosensitivity to articular cartilage. Proc Natl Acad Sci U S A, 2014, 111(47): E5114-E5122.
12.	Khatib N S, Monsen J, Ahmed S, et al. Mechanoregulatory role of TRPV4 in prenatal skeletal development. Sci Adv, 2023, 9(4): eade2155.
13.	White J P M, Cibelli M, Urban L, et al. TRPV4: molecular conductor of a diverse orchestra. Physiol Rev, 2016, 96(3): 911-973.
14.	Liebe F, Liebe H, Sponder G, et al. Effects of butyrate- on ruminal Ca²⁺ transport: evidence for the involvement of apically expressed TRPV3 and TRPV4 channels. Pflugers Arch, 2022, 474(3): 315-342.
15.	Lewis R, Purves G, Crossley J, et al. Modelling the membrane potential dependence on non-specific cation channels in canine articular chondrocytes. Biophys J, 2010, 98(3): 340a.
16.	Krupkova O, Zvick J, Wuertz-Kozak K. The role of transient receptor potential channels in joint diseases. Eur Cell Mater, 2017, 34: 180-201.
17.	Sianati S, Schroeter L, Richardson J, et al. Modulating the mechanical activation of TRPV4 at the cell-substrate interface. Front Bioeng Biotechnol, 2021, 8: 608951.
18.	Hattori K, Takahashi N, Terabe K, et al. Activation of transient receptor potential vanilloid 4 protects articular cartilage against inflammatory responses via CaMKK/AMPK/NF-κB signaling pathway. Sci Rep, 2021, 11(1): 1-9.
19.	Servin-Vences M R, Moroni M, Lewin G R, et al. Direct measurement of TRPV4 and PIEZO1 activity reveals multiple mechanotransduction pathways in chondrocytes. Elife, 2017, 6: e21074.
20.	沈雪, 张琥, 薛艳, 等. 瞬时受体电位香草素受体4与骨关节炎关系的研究进展. 中医正骨, 2020, 32(8): 30-33.
21.	O’Conor C J, Griffin T M, Liedtke W, et al. Increased susceptibility of Trpv4-deficient mice to obesity and obesity-induced osteoarthritis with very high-fat diet. Ann Rheum Dis, 2013, 72: 300-304.
22.	Guilak F, Leddy H A, Liedtke W. Transient receptor potential vanilloid 4: The sixth sense of the musculoskeletal system? Ann N Y Acad Sci, 2010, 1192: 404-409.
23.	Zhang K, Wang L, Liu Z, et al. Mechanosensory and mechanotransductive processes mediated by ion channels in articular chondrocytes: Potential therapeutic targets for osteoarthritis. Channels, 2021, 15(1): 339-359.
24.	张力, 王培民, 殷松江, 等. TRPV4通道在膝骨关节炎软骨细胞中的功能表达. 中国现代医学杂志, 2019, 29(23): 17-22.
25.	Savadipour A, Nims R J, Katz D B, et al. Regulation of chondrocyte biosynthetic activity by dynamic hydrostatic pressure: the role of TRP channels. Connect Tissue Res, 2022, 63(1): 69-81.
26.	Fu S, Meng H, Inamdar S, et al. Activation of TRPV4 by mechanical, osmotic or pharmaceutical stimulation is anti-inflammatory blocking IL-1β mediated articular cartilage matrix destruction. Osteoarthr Cartil, 2021, 29(1): 89-99.
27.	Willard V P, Leddy H A, Palmer D, et al. Transient receptor potential vanilloid 4 as a regulator of induced pluripotent stem cell chondrogenesis. Stem Cells, 2021, 39(11): 1447-1456.
28.	Song H, Park K H. Regulation and function of SOX9 during cartilage development and regeneration. Semin Cancer Biol, 2020, 67(Pt 1): 12-23.
29.	Trompeter N, Gardinier J D, DeBarros V, et al. Insulin-like growth factor-1 regulates the mechanosensitivity of chondrocytes by modulating TRPV4. Cell Calcium, 2021, 99: 102467.
30.	Agarwal P, Lee H, Smeriglio P, et al. A dysfunctional TRPV4–GSK3β pathway prevents osteoarthritic chondrocytes from sensing changes in extracellular matrix viscoelasticity. Nat Biomed Eng, 2021, 5(12): 1472-1484.
31.	Coste B, Mathur J, Schmidt M, et al. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science, 2010, 330(6000): 55-60.
32.	Lee W, Nims R J, Savadipour A, et al. Inflammatory signaling sensitizes Piezo1 mechanotransduction in articular chondrocytes as a pathogenic feed-forward mechanism in osteoarthritis. Proc Natl Acad Sci U S A, 2021, 118(13): e2001611118.
33.	Savadipour A, Palmer D, Ely E V, et al. The role of PIEZO ion channels in the musculoskeletal system. Am J Physiol Cell Physiol, 2023, 324(3): C728-C740.
34.	Delco M L, Bonassar L J. Targeting calcium-related mechanotransduction in early OA. Nat Rev Rheumatol, 2021, 17(8): 445-446.
35.	Nims R J, Pferdehirt L, Ho N B, et al. A synthetic mechanogenetic gene circuit for autonomous drug delivery in engineered tissues. Sci Adv, 2021, 7(5): eabd9858.
36.	Sukharev S, Corey D P. Mechanosensitive channels: multiplicity of families and gating paradigms. Science’s STKE, 2004, 2004(219): re4.
37.	Kung C. A possible unifying principle for mechanosensation. Nature, 2005, 436(7051): 647-654.
38.	Wang J, Jiang J, Yang X, et al. Tethering Piezo channels to the actin cytoskeleton for mechanogating via the cadherin-β-catenin mechanotransduction complex. Cell Rep, 2022, 38(6): 110342.
39.	Jackson W F. Calcium-dependent ion channels and the regulation of arteriolar myogenic tone. Front Physiol, 2021, 12: 770450.
40.	Krieg M, Dunn A R, Goodman M B. Mechanical control of the sense of touch by β-spectrin. Nat Cell Biol, 2014, 16(3): 224-233.
41.	Kobayashi T, Sokabe M. Sensing substrate rigidity by mechanosensitive ion channels with stress fibers and focal adhesions. Curr Opin Cell Biol, 2010, 22: 669-676.
42.	Boos M A, Lamandé S R, Stok K S. Multiscale strain transfer in cartilage. Front Cell Dev Biol, 2022, 10: 795522.
43.	Servin‐Vences M R, Richardson J, Lewin G R, et al. Mechanoelectrical transduction in chondrocytes. Clin Exp Pharmacol Physiol, 2018, 45(5): 481-488.
44.	Jin H, Jiang S, Wang R, et al. Mechanistic insight into the roles of integrins in osteoarthritis. Front Cell Dev Biol, 2021, 9: 693484.
45.	Dieterle M P, Husari A, Rolauffs B, et al. Integrins, cadherins and channels in cartilage mechanotransduction: perspectives for future regeneration strategies. Expert Rev Mol Med, 2021, 23: e14.
46.	De Belly H, Paluch E K, Chalut K J. Interplay between mechanics and signalling in regulating cell fate. Nat Rev Mol Cell Biol, 2022, 23(7): 465-480.
47.	Cox C D, Bavi N, Martinac B. Origin of the force: The force-from-lipids principle applied to Piezo channels. Curr Top Membr, 2017, 79: 59-96.
48.	Du G, Li L, Zhang X, et al. Roles of TRPV4 and piezo channels in stretch-evoked Ca²⁺ response in chondrocytes. Exp Biol Med, 2020, 245(3): 180-189.
49.	Lee H P, Stowers R, Chaudhuri O. Volume expansion and TRPV4 activation regulate stem cell fate in three-dimensional microenvironments. Nat Commun, 2019, 10(1): 529.
50.	Wei L, Mousawi F, Li D, et al. Adenosine Triphosphate release and P2 receptor signaling in piezo1 channel-dependent mechanoregulation. Front Pharmacol, 2019, 10: 1304.
51.	张全有, 陈维毅. 从基质黏弹性和钙信号深入理解骨性关节炎发病机制. 医用生物力学, 2022, 37(1): 1-2.

1. Han S. Osteoarthritis year in review 2022: biology. Osteoarthr Cartil, 2022, 30(12): 1575-1582.
2. Ching K, Houard X, Berenbaum F, et al. Hypertension meets osteoarthritis-revisiting the vascular aetiology hypothesis. Nat Rev Rheumatol, 2021, 17(9): 533-549.
3. Gao W, Hasan H, Anderson D E, et al. The role of mechanically-activated ion channels Piezo1, Piezo2, and TRPV4 in chondrocyte mechanotransduction and mechano-therapeutics for osteoarthritis. Front Cell Dev Biol, 2022: 1002.
4. Guilak F, Nims R J, Dicks A, et al. Osteoarthritis as a disease of the cartilage pericellular matrix. Matrix Biol, 2018, 71-72: 40-50.
5. Jiang W, Liu H, Wan R, et al. Mechanisms linking mitochondrial mechanotransduction and chondrocyte biology in the pathogenesis of osteoarthritis. Ageing Res Rev, 2021, 67: 101315.
6. Hodgkinson T, Kelly D C, Curtin C M, et al. Mechanosignalling in cartilage: an emerging target for the treatment of osteoarthritis. Nat Rev Rheumatol, 2022, 18(2): 67-84.
7. Zhang M, Meng N, Wang X, et al. TRPV4 and PIEZO channels mediate the mechanosensing of chondrocytes to the biomechanical microenvironment. Membranes, 2022, 12(2): 237.
8. Martinac B. 2021 Nobel Prize for mechanosensory transduction. Biophys Rev, 2022, 14(1): 15-20.
9. Corey D P, Hudspeth A J. Ionic basis of the receptor potential in a vertebrate hair cell. Nature, 1979, 281(5733): 675-677.
10. Phan M N, Leddy H A, Votta B J, et al. Functional characterization of TRPV4 as an osmotically sensitive ion channel in porcine articular chondrocytes. Arthritis Rheum, 2009, 60(10): 3028-3037.
11. Lee W, Leddy H A, Chen Y, et al. Synergy between Piezo1 and Piezo2 channels confers high-strain mechanosensitivity to articular cartilage. Proc Natl Acad Sci U S A, 2014, 111(47): E5114-E5122.
12. Khatib N S, Monsen J, Ahmed S, et al. Mechanoregulatory role of TRPV4 in prenatal skeletal development. Sci Adv, 2023, 9(4): eade2155.
13. White J P M, Cibelli M, Urban L, et al. TRPV4: molecular conductor of a diverse orchestra. Physiol Rev, 2016, 96(3): 911-973.
14. Liebe F, Liebe H, Sponder G, et al. Effects of butyrate- on ruminal Ca²⁺ transport: evidence for the involvement of apically expressed TRPV3 and TRPV4 channels. Pflugers Arch, 2022, 474(3): 315-342.
15. Lewis R, Purves G, Crossley J, et al. Modelling the membrane potential dependence on non-specific cation channels in canine articular chondrocytes. Biophys J, 2010, 98(3): 340a.
16. Krupkova O, Zvick J, Wuertz-Kozak K. The role of transient receptor potential channels in joint diseases. Eur Cell Mater, 2017, 34: 180-201.
17. Sianati S, Schroeter L, Richardson J, et al. Modulating the mechanical activation of TRPV4 at the cell-substrate interface. Front Bioeng Biotechnol, 2021, 8: 608951.
18. Hattori K, Takahashi N, Terabe K, et al. Activation of transient receptor potential vanilloid 4 protects articular cartilage against inflammatory responses via CaMKK/AMPK/NF-κB signaling pathway. Sci Rep, 2021, 11(1): 1-9.
19. Servin-Vences M R, Moroni M, Lewin G R, et al. Direct measurement of TRPV4 and PIEZO1 activity reveals multiple mechanotransduction pathways in chondrocytes. Elife, 2017, 6: e21074.
20. 沈雪, 张琥, 薛艳, 等. 瞬时受体电位香草素受体4与骨关节炎关系的研究进展. 中医正骨, 2020, 32(8): 30-33.
21. O’Conor C J, Griffin T M, Liedtke W, et al. Increased susceptibility of Trpv4-deficient mice to obesity and obesity-induced osteoarthritis with very high-fat diet. Ann Rheum Dis, 2013, 72: 300-304.
22. Guilak F, Leddy H A, Liedtke W. Transient receptor potential vanilloid 4: The sixth sense of the musculoskeletal system? Ann N Y Acad Sci, 2010, 1192: 404-409.
23. Zhang K, Wang L, Liu Z, et al. Mechanosensory and mechanotransductive processes mediated by ion channels in articular chondrocytes: Potential therapeutic targets for osteoarthritis. Channels, 2021, 15(1): 339-359.
24. 张力, 王培民, 殷松江, 等. TRPV4通道在膝骨关节炎软骨细胞中的功能表达. 中国现代医学杂志, 2019, 29(23): 17-22.
25. Savadipour A, Nims R J, Katz D B, et al. Regulation of chondrocyte biosynthetic activity by dynamic hydrostatic pressure: the role of TRP channels. Connect Tissue Res, 2022, 63(1): 69-81.
26. Fu S, Meng H, Inamdar S, et al. Activation of TRPV4 by mechanical, osmotic or pharmaceutical stimulation is anti-inflammatory blocking IL-1β mediated articular cartilage matrix destruction. Osteoarthr Cartil, 2021, 29(1): 89-99.
27. Willard V P, Leddy H A, Palmer D, et al. Transient receptor potential vanilloid 4 as a regulator of induced pluripotent stem cell chondrogenesis. Stem Cells, 2021, 39(11): 1447-1456.
28. Song H, Park K H. Regulation and function of SOX9 during cartilage development and regeneration. Semin Cancer Biol, 2020, 67(Pt 1): 12-23.
29. Trompeter N, Gardinier J D, DeBarros V, et al. Insulin-like growth factor-1 regulates the mechanosensitivity of chondrocytes by modulating TRPV4. Cell Calcium, 2021, 99: 102467.
30. Agarwal P, Lee H, Smeriglio P, et al. A dysfunctional TRPV4–GSK3β pathway prevents osteoarthritic chondrocytes from sensing changes in extracellular matrix viscoelasticity. Nat Biomed Eng, 2021, 5(12): 1472-1484.
31. Coste B, Mathur J, Schmidt M, et al. Piezo1 and Piezo2 are essential components of distinct mechanically activated cation channels. Science, 2010, 330(6000): 55-60.
32. Lee W, Nims R J, Savadipour A, et al. Inflammatory signaling sensitizes Piezo1 mechanotransduction in articular chondrocytes as a pathogenic feed-forward mechanism in osteoarthritis. Proc Natl Acad Sci U S A, 2021, 118(13): e2001611118.
33. Savadipour A, Palmer D, Ely E V, et al. The role of PIEZO ion channels in the musculoskeletal system. Am J Physiol Cell Physiol, 2023, 324(3): C728-C740.
34. Delco M L, Bonassar L J. Targeting calcium-related mechanotransduction in early OA. Nat Rev Rheumatol, 2021, 17(8): 445-446.
35. Nims R J, Pferdehirt L, Ho N B, et al. A synthetic mechanogenetic gene circuit for autonomous drug delivery in engineered tissues. Sci Adv, 2021, 7(5): eabd9858.
36. Sukharev S, Corey D P. Mechanosensitive channels: multiplicity of families and gating paradigms. Science’s STKE, 2004, 2004(219): re4.
37. Kung C. A possible unifying principle for mechanosensation. Nature, 2005, 436(7051): 647-654.
38. Wang J, Jiang J, Yang X, et al. Tethering Piezo channels to the actin cytoskeleton for mechanogating via the cadherin-β-catenin mechanotransduction complex. Cell Rep, 2022, 38(6): 110342.
39. Jackson W F. Calcium-dependent ion channels and the regulation of arteriolar myogenic tone. Front Physiol, 2021, 12: 770450.
40. Krieg M, Dunn A R, Goodman M B. Mechanical control of the sense of touch by β-spectrin. Nat Cell Biol, 2014, 16(3): 224-233.
41. Kobayashi T, Sokabe M. Sensing substrate rigidity by mechanosensitive ion channels with stress fibers and focal adhesions. Curr Opin Cell Biol, 2010, 22: 669-676.
42. Boos M A, Lamandé S R, Stok K S. Multiscale strain transfer in cartilage. Front Cell Dev Biol, 2022, 10: 795522.
43. Servin‐Vences M R, Richardson J, Lewin G R, et al. Mechanoelectrical transduction in chondrocytes. Clin Exp Pharmacol Physiol, 2018, 45(5): 481-488.
44. Jin H, Jiang S, Wang R, et al. Mechanistic insight into the roles of integrins in osteoarthritis. Front Cell Dev Biol, 2021, 9: 693484.
45. Dieterle M P, Husari A, Rolauffs B, et al. Integrins, cadherins and channels in cartilage mechanotransduction: perspectives for future regeneration strategies. Expert Rev Mol Med, 2021, 23: e14.
46. De Belly H, Paluch E K, Chalut K J. Interplay between mechanics and signalling in regulating cell fate. Nat Rev Mol Cell Biol, 2022, 23(7): 465-480.
47. Cox C D, Bavi N, Martinac B. Origin of the force: The force-from-lipids principle applied to Piezo channels. Curr Top Membr, 2017, 79: 59-96.
48. Du G, Li L, Zhang X, et al. Roles of TRPV4 and piezo channels in stretch-evoked Ca²⁺ response in chondrocytes. Exp Biol Med, 2020, 245(3): 180-189.
49. Lee H P, Stowers R, Chaudhuri O. Volume expansion and TRPV4 activation regulate stem cell fate in three-dimensional microenvironments. Nat Commun, 2019, 10(1): 529.
50. Wei L, Mousawi F, Li D, et al. Adenosine Triphosphate release and P2 receptor signaling in piezo1 channel-dependent mechanoregulation. Front Pharmacol, 2019, 10: 1304.
51. 张全有, 陈维毅. 从基质黏弹性和钙信号深入理解骨性关节炎发病机制. 医用生物力学, 2022, 37(1): 1-2.

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