Previous research in health and disease focussed primarily on biochemical signals coming from cells including cytokines and chemokines, hormones, growth factors and small peptides, neurotransmitters, fatty acids and their derivatives, and dissolved gases. However, current research confirms that cells and their signalling molecules do not operate in isolation but within complex, dynamic and interdependent systems that include additional levels of control, such as physical and mechanical signalling provided by the extracellular matrix (ECM).[1]
The functions of the ECM include not only structural support but also active control of vital physiological processes, including normal formation and development of tissues,[2] immunity including inflammation,[3] cellular metabolism[4], and insulin sensitivity in pancreatic islet cells.[5] In order to perform its physiological functions, ECM needs highly controlled remodelling, maintaining a dynamic balance between the “right” timing, “right” amount, and “right” location of degradation and growth.[6] Abnormal ECM remodelling is part of the pathophysiology of numerous diseases including osteoarthritis, vascular diseases such as hypertension, atherosclerosis, and lower extremity venous diseases, cardiovascular disease, cardiomyopathy, diseases associated with fibrosis of the lung, liver and kidney, as well as neurodegenerative diseases such as Alzheimer’s disease.6 Most recently, metabolic diseases such obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease (MASLD)[1]were demonstrated to be associated with improperly controlled ECM remodelling. [7] Destruction of lung alveolar tissue due to impaired ECM remodelling could also impair microcirculation and chronically reduce perfusion, leading to some of the symptoms of severe COVID-19 and long COVID in some patients.[8] The relative stiffness and compliance of the ECM also helps control immune cell functions and wound healing [9] and promotes cancer progression if it is not tightly controlled.[10]
The recognition that ECM also has critical regulatory roles in health and disease suggests that clinical strategies to support healthy ECM should be included as part of comprehensive clinical care. For example, potential sources of ongoing damage to the ECM, such as environmental toxicants, excessive free radicals, and chronic non-resolving inflammation, could be minimized or reduced through informed avoidance of causative agents and/or via regular detoxification using herbal medicines or dietary or nutritional supplements. Healthy ECM remodelling also can be supported using therapeutics that promote lymphatic drainage, such as special massage techniques, skin brushing, hot-cold contrast baths, or by using appropriate herbal medicines and low dose complex medications. Supplementing with different proteolytic enzymes (e.g. papain, bromelain, nattokinase, lumbrokinase, serratiopeptidase) could also help restore normal ECM. Finally, manual therapies and stretching to promote normal tissue laxity could also impact inflammation resolution in connective tissue and help restore homeostasis.[11]
Current scientific evidence indicates that a close reciprocal relationship exists between the cell and ECM. Unhealthy cells cannot make a healthy ECM, and vice versa, without a healthy ECM it is impossible to have healthy cells. Dysfunction of both cells and the ECM they reside in needs to be addressed by naturopathic doctors to restore and maintain longer term health and prevent disease.
Manou D, Caon I et al., The Complex Interplay Between Extracellular Matrix and Cells in Tissues. Methods Mol Biol. 2019;1952:1-20.
Díaz-de-la-Loza MD, Stramer BM. The extracellular matrix in tissue morphogenesis: No longer a backseat driver. Cells Dev. 2024 Mar;177:203883
Sutherland TE, Dyer DP, Allen JE. The extracellular matrix and the immune system: A mutually dependent relationship. Science. 2023 Feb 17;379(6633):eabp8964
Ge H, Tian M et al., Extracellular Matrix Stiffness: New Areas Affecting Cell Metabolism. Front Oncol. 2021 Feb 24;11:631991
Johansen CG, Holcomb K et al., Extracellular matrix stiffness mediates insulin secretion in pancreatic islets via mechanosensitive Piezo1 channel regulated Ca2+dynamics. Matrix Biol Plus. 2024 May 17;22:100148
Bonnans C, Chou J, Werb Z. Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol. 2014 Dec;15(12):786-801
Beddows CA, Shi F et al., Pathogenic hypothalamic extracellular matrix promotes metabolic disease. Nature. 2024 Sep;633(8031):914-922
Narasaraju T, Neeli I, et al., Neutrophil Activity and Extracellular Matrix Degradation: Drivers of Lung Tissue Destruction in Fatal COVID-19 Cases and Implications for Long COVID. Biomolecules. 2024 Feb 17;14(2):236.
Diller RB, Tabor AJ. The Role of the Extracellular Matrix (ECM) in Wound Healing: A Review. Biomimetics (Basel). 2022 Jul 1;7(3):87
Najafi M, Farhood B, Mortezaee K. Extracellular matrix (ECM) stiffness and degradation as cancer drivers. J Cell Biochem. 2019 Mar;120(3):2782-2790
Berrueta L, Muskaj I et al., Stretching Impacts Inflammation Resolution in Connective Tissue. J Cell Physiol. 2016 Jul;231(7):1621-7
