Understanding Fascial Tissue on the Molecular Level—How Its Unique Properties Enable Adaptation or Dysfunction

Academic Editor: Carla Stecco Received: 11 November 2025 Revised: 11 December 2025 Accepted: 14 December 2025 Published: 23 December 2025 Copyright: © 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license. Review Understanding Fascial Tissue on the Molecular Level—How Its Unique Properties Enable Adaptation or Dysfunction Karen B. Kirkness 1,* and Suzanne Scarlata 2 1Health Professions Education Unit, Hull York Medical School, York YO10 5DD, UK 2Department of Chemistry and Biochemistry, Worcester Polytechnic Institute, Worcester, MA 01609, USA; [email protected] *Correspondence: kar[email protected] Abstract Despite extensive research on fascial mechanobiology, no unified mechanotransduction framework has been established to explain how mechanical forces translate into adaptive cellular responses in fascial tissue. This narrative review synthesizes evidence from mesenchymal cell and fibroblast research to propose the Ca 2+ –Hyaluronan (CHA) axis as a comprehensive mechanotransduction feedback loop for fascia phenomenology. The CHA framework describes how mechanical stress activates Ca 2+ channels (Piezo1, TRPV4, P2Y2), triggering HAS2-mediated hyaluronan (HA) synthesis. The molecular weight of synthesized HA then determines receptor signaling outcomes: high-molecular-weight HA binds CD44 to promote tissue stability and quiescence, while low-molecular-weight HA fragments activate RHAMM to drive remodeling and repair—a dynamic oscillation termed “Quiet or Riot.” Three key conclusions emerge: First, the CHA framework is well supported by existing literature on mesenchymal cells, providing a testable model for fascial mechanobiology. Second, HA molecular weight dynamics and CD44/RHAMM oscillation have direct implications for optimizing movement, manual therapy, and rehabilitative interventions. Third, while HA-CD44/RHAMM signaling is broadly implicated in tissue remodeling, Ca 2+ -dependent regulatory mechanisms specific to fasciacytes require experimental validation. A critical translational gap remains: the absence of quantitative mechanical thresholds distinguishing beneficial from pathological loading limits clinical application. Future research should employ 3D matrix models, live imaging, receptor manipulation, and omics profiling to establish these thresholds and validate the CHA framework in fasciacytes. Understanding fascial mechanotransduction through the CHA loop may transform approaches to movement prescription, manual therapy, and treatment of fascial dysfunction. Keywords: calcium signaling; HAS2; hyaluronic acid; fascia; mechanotransduction; extracellular matrix; tissue adaptation; morphogenetic field; CD44; fasciacytes 1. Introduction 1.1. HA in Fascia: Structure, Function, and Cellular Sources Recent literature recognizes fascia as a globally distributed, highly specialized connective tissue with both fibrous and gel-like hyaluronic acid (HA) components, reflecting its diverse anatomical and functional roles [ 1 – 3 ]. HA is a key functional component of the extracellular matrix (ECM) that supports cellular structure. It is an evolutionarily Int. J. Mol. Sci. 2026,27, 160 https://doi.org/10.3390/ijms27010160 Int. J. Mol. Sci. 2026,27, 160 2 of 19 ancient and highly conserved polysaccharide found across a wide range of organisms, from bacteria to vertebrates, underscoring its fundamental biological importance [4,5]. HA’s unique physicochemical properties—including its capacity to bind up to 1000 times its weight in water, its viscoelastic behavior, and its role in cell signaling—make it essential for maintaining tissue hydration and modulating cellular responses to mechanical and biochemical stimuli [ 6 – 8 ]. HA is abundant in the loose connective tissue of fascia, facilitating gliding in fascial planes, and supporting viscoelasticity and tissue adaptability [ 9 – 11 ]. The amount, weight, and properties of HA in fascia vary by anatomical site, correlating with the degree of required tissue gliding and mechanical function [9,12]. See Figure 1. Figure 1. Chemical properties of hyaluronic acid (HA). (A) structure of HA showing that it is a linear polysaccharide composed of repeating disaccharide units of β -1,4-D-glucuronic acid and β -1,3-N-acetyl-D-glucosamine. (B) Chemical reaction showing the catalysis by HAS involves the polymerization of hyaluronic acid (HA) from two sugar nucleotide substrates, UDP-N-acetylglucosamine and UDP-glucuronic acid. Specialized cells called fasciacytes—recently identified as distinct from fibroblasts— are dedicated to producing HA-rich ECM, with high expression of the HAS2 gene (see below), which synthesizes high molecular weight HA crucial for hydration and homeostasis [3,13,14]. The amount and properties of HA in fascia vary by anatomical site, correlating with the degree of required tissue gliding and mechanical function. 1.2. HAS2: The Key Contributor of Normal HA in the ECM The synthesis of HA is catalyzed by three hyaluronan synthase isoforms (HAS1,HAS2, and HAS3), among which HAS2 demonstrates unique regulatory properties and tissuespecific expression patterns. HAS2 is the key isoform responsible for producing high molecular weight HA essential ECM homeostasis. All mesenchymal cells express HAS1/2/3, but HAS2 concentration is by far the highest and linked to normal ECM function. Research on HAS2 is most extensive in fibroblasts and mesenchymal stem cells (MSCs), reflecting their central roles in tissue repair, ECM production, and immunomodulation [15,16]. See Figure 2. 1.3. HAS2-Expressing Cells: From Fibroblasts to Fasciacytes The grouping of fibroblasts and mesenchymal stem cells (MSCs) as primary research models is scientifically justified given their striking similarity. These cell types are often indistinguishable by standard laboratory criteria, sharing morphology, surface markers, gene expression, and differentiation potential, as both can differentiate into adipocytes, chondrocytes, and osteoblasts, and both exhibit immunomodulatory properties [ 17 – 21 ]. Some researchers propose that fibroblasts may represent a differentiated or aged form of MSCs, or that MSCs are a specialized subset of fibroblasts, further supporting the validity of using findings from one cell type to inform understanding of the other. https://doi.org/10.3390/ijms27010160 Int. J. Mol. Sci. 2026,27, 160 3 of 19 Figure 2. Anatomy of fascia. (Left)—Cartoon of layers above muscles showing the location of fascia. (Right)—Fascia organization. Image created with BioRender.com, accessed on 11 November 2025. Fasciacytes are a distinct cell type within fascia characterized by the highest expression of HAS2, which differentiates them functionally from classical fibroblasts and MSCs [ 22 ]. While fasciacytes share some markers with fibroblasts, such as vimentin positivity, they exhibit unique morphological features and express markers like S-100A4, suggesting a specialized role in producing the HA-rich ECM critical for fascial gliding. Fibroblasts and MSCs also produce HA via HAS2, which regulates processes like cell migration, senescence, and fibrosis, but their HAS2 expression and HA signaling roles vary by tissue context and pathological state [23,24]. 1.4. Fascia Mechanotransduction: Multiple Pathways Fibroblasts have been shown to orchestrate fascia’s structural integrity, mechanical responsiveness, and repair processes through HA extrusion, ECM synthesis, contractility, and interaction with immune signals [ 12 , 25 , 26 ]. Fascial tissues rapidly adapt to mechanical demands through such autonomous, cell-intrinsic mechanotransduction mechanisms. Key mechanosensors in fascia that have long dominated the literature include focal adhesions (FAs), integrin-associated complexes that link the extracellular matrix (ECM) to the cytoskeleton and transduce mechanical signals into biochemical responses, regulating cell adhesion, cytoskeletal remodeling, and gene expression [27–29]. 1.5. YAP as a Downstream Mechanotransducer Recent evidence highlights Yes-Associated Protein (YAP) as a key mechanotransducer in deep fascia fibroblasts, where mechanical stimulation activates YAP signaling to promote ECM remodeling and fibrogenesis [ 30 , 31 ]. In thoracolumbar fascia fibroblasts, mechanical stimuli increase active YAP, upregulating collagen and hyaluronan-binding protein (HABP2) expression, creating a feed-forward loop where YAP-driven ECM deposition increases matrix stiffness, further activating mechanosensitive pathways [ 32 ]. This positions YAP as a central downstream effector translating mechanical stimuli into profibrotic gene expression, linking tissue homeostasis and pathological states such as fibrosis and myofascial pain [33–35]. 1.6. HA: The Global Mechanotransductive Gel HA molecular weight modulates cellular signaling across multiple cell types [ 36 – 38 ] where high molecular weight (HMW) HA increases tissue stiffness while fragmentation produces low molecular weight (LMW) HA that promotes inflammation [ 11 , 39 ]. However, direct evidence for differential YAP responses to HMW versus LMW HA specifically in https://doi.org/10.3390/ijms27010160 Int. J. Mol. Sci. 2026,27, 160 4 of 19 fascia fibroblasts remains limited. Researchers have explicitly acknowledged this gap and the “widespread fog” regarding HA molecular weight effects on specific biological processes, particularly YAP/TAZ signaling in tissue-specific contexts [36,40,41]. 1.7. Aims and Scope of This Review HA is predominantly viewed as a passive gel substrate for tissue hydration and lubrication. Here, we argue that HA is an active participant in mechanotransduction. Despite extensive evidence of HA molecular weight’s influence on cellular adaptation and the critical importance of Ca 2+ -mediated mechanotransduction in fascial function, no comprehensive biochemical feedback loop has been proposed. We aim to demonstrate that the evidence integrating mechanical stress, calcium signaling, HA synthesis, and molecular-weight-dependent receptor signaling has been clearly established in cell types relevant to fascia research. This review argues that the Ca 2+ -HA (CHA) axis provides the missing unified framework. CHA identifies the molecular pathway in which HA functions not merely as a structural matrix but also as a central signaling molecule whose molecular weight orchestrates oscillations between tissue adaptation and homeostasis. The scope of this framework is supported by abundant research on mesenchymal cells, positioning HA as integral to fascial mechanobiology. It offers a testable model for understanding tissue responses to mechanical loading, relevant to clinicians, movement educators, and manual therapists. 2. The Calcium-HA (CHA) Axis: Overview 2.1. The CHA Axis: The Mechanotransduction Feedback Loop in Fascia As detailed below, HA synthesis is regulated by intracellular Ca 2+ levels that are mobilized by several mechanical cues. We propose that the tight coupling between Ca 2+ - dependent pathways and HAS1/2/3 expression represents a fundamental principle that enables fascia to function as a responsive, adaptive tissue interface that operates largely independently of higher-level neural or endocrine control. This hypothesis is based on evidence from multiple research domains, including mechanobiology, cell signaling, tissue engineering, and developmental biology. 2.2. The Fundamental Role of Calcium in Cell Signaling Calcium ions (Ca 2+ ) function as one of biology’s most versatile and ubiquitous second messengers, capable of translating diverse environmental stimuli into rapid, coordinated cellular responses [ 42 ]. The use of Ca 2+ as a signaling molecule exploits several unique properties. Its low resting intracellular concentration (typically ~100 nM) compared to extracellular levels (~1–2 mM) creates a steep electrochemical gradient. Its ability to bind rapidly and reversibly to numerous proteins, altering their conformation and activity, enables cellular responses. The existence of highly conserved cellular machinery has evolved across the kingdoms of life to generate, propagate, and terminate Ca 2+ signals with precise spatiotemporal control [43]. In the context of tissue adaptation and ECM remodeling, Ca 2+ signaling serves as an integration point for multiple stimulus modalities. Mechanical forces, detected by mechanosensitive ion channels and integrin-mediated adhesions, can trigger Ca 2+ influx directly [ 44 ]. Chemical signals, including ATP released from stressed or damaged cells, activate G-protein coupled receptors that mobilize intracellular Ca2+ stores [45]. 2.3. Calcium-Driven HA Synthesis as Mechanical Adaptation Elevated Ca 2+ activates the HAS2 signaling cascade leading to increased HA synthesis within hours. Because of its extraordinary water-binding capacity, this newly synthesized https://doi.org/10.3390/ijms27010160 Int. J. Mol. Sci. 2026,27, 160 5 of 19 HA increases tissue hydration. This hydration distributes mechanical loads more evenly, protecting against compressive damage [ 6 ], contributing to the viscosity buffering properties of the fluid between fascial planes, easing movement. HA influences cell adhesion, migration, and signaling through its interactions with CD44, RHAMM, and other receptors, facilitating tissue remodeling and repair [46]. Thus, the HAS2 pathway represents a form of real-time mechanical adaptation. We argue that fascia “feels” the increased mechanical demand and immediately increases production of its primary hydrating molecule. The system operates as a self-lubricating bearing: when mechanical demand increases, the system automatically produces more lubricant. 3. Mechanotransduction and Calcium Signaling 3.1. Mechanical Forces as Primary Fascial Stimuli Mechanical forces represent perhaps the most constant and physiologically relevant stimulus for fascial tissues. Every movement, posture change, and load-bearing activity generates mechanical strains that must be sensed and responded to maintain tissue integrity and function. Cells detect mechanical forces through multiple mechanisms, including stretch-activated Ca 2+ channels, integrin-mediated adhesions that link the cytoskeleton to the ECM, and primary cilia that act as mechanical antennae [44,47]. Many mechanosensing mechanisms directly or indirectly modulate intracellular Ca 2+ levels, establishing a critical link between mechanical stimulation and cellular biochemical responses. Mechanically gated (stretch-sensitive) Ca 2+ channels embedded in the plasma membrane allow Ca 2+ influx in direct proportion to membrane deformation, essentially converting mechanical force into an ionic signal. The magnitude and duration of Ca 2+ entry through these channels depend on both the intensity and persistence of the applied mechanical stress as shown in Figure 3and described in Table 1. Table 1. Relationship between mechanical stress parameters and Ca2+ entry responses. Mechanical Stress Parameter Ca2+ Entry Response Example Systems Citations Low intensity, brief Minimal or transient Ca2+ influx Astrocytes, neurons [48–50] High intensity, brief Large, rapid Ca2+ spike Platelets, astrocytes [49–51] Sustained/repetitive Prolonged or cumulative Ca2+ entry Endothelial, neurons [48–50,52] 3.2. Dose–Response: Intensity and Duration of Mechanical Stress Higher levels of mechanical stress (e.g., greater shear force or stretch amplitude) result in larger and more sustained increases in intracellular Ca 2+ . This dose-dependent Ca 2+ response directly translates to proportional HAS2 activation [ 53 ], as intense stress generates high Ca 2+ signals that activate signaling molecules which allow cellular memory and greater HAS2 transcription. Tissues experiencing higher mechanical loads thus produce more HA, exactly when and where it is needed most [54]. The duration of mechanical stress application also shapes the Ca 2+ response: short, intense pulses trigger transient Ca 2+ spikes, while sustained or repetitive stress leads to prolonged or cumulative Ca 2+ elevations [ 48 , 49 ]. The temporal pattern of Ca 2+ signaling determines how long HAS2 remains upregulated. Transient Ca 2+ spikes from brief stress trigger short bursts of HAS2 expression that self-terminate through negative feedback (ATP → adenosine) [ 34 , 52 – 54 ], whereas sustained or repetitive stress maintains elevated Ca 2+ longer, prolonging HAS2 activation and producing more sustained HA synthesis. This temporal sensitivity prevents the system from wasting resources responding to trivial, momentary perturbations while mounting robust responses to persistent mechanical challenges. https://doi.org/10.3390/ijms27010160 Int. J. Mol. Sci. 2026,27, 160 6 of 19 Figure 3. The CHA feedback loop in Fascia. Mechanical forces (stretch, pressure, shear stress) deform mesenchymal cells, initiating a biochemical feedback loop that links mechanical stimuli to hyaluronan synthesis and cellular adaptation. Mechanosensitive calcium channels (Piezo1/2, TRPV4) are activated by mechanical deformation [ 12 , 55 – 58 ], leading to rapid Ca 2+ influx and elevated intracellular calcium levels [ 45 , 57 , 59 ], which then sets off signaling cascades that lead to the upregulation of HAS1/2/3 and HA synthesis [ 45 , 55 , 57 , 60 ]. Newly synthesized HA is extruded into the ECM, where it increases ECM hydration and is sensed by CD44 and RHAMM receptors on the cell surface, which modulate further HAS expression and cellular responses, creating a self-regulating feedback loop [12,55,57]. Image created with BioRender.com, accessed on 11 November 2025. 3.3. Mechanosensitive Channel Diversity Three primary mechanosensitive Ca 2+ channels—Piezo1, TRPV4, and TRPC5—work in concert to provide fascial cells with a nuanced capacity to detect diverse mechanical stimuli (Table 2). Cells can express unique combinations of mechanosensitive channels, allowing them to be “tuned” to the dominant mechanical forces in their microenvironment—some regions more responsive to shear (Piezo1/TRPV4) and others to stretch or compression (Piezo1/TRPC5). This channel diversity enables different fascial regions to calibrate their HAS2 response, resulting in spatially appropriate HA synthesis and lubrication tailored to local mechanical demands. Table 2. Mechanosensitive Channel Tuning and Functional Outcomes. How different mechanosensitive channels tune Ca2+-HAS2 responses in fascia. Channel Mechanical Stimuli Sensed Tissue/Cell Specificity Functional Outcome in Fascia Citations Piezo1 Shear, stretch, compression Widely expressed, force sensors Initiates Ca 2+ influx, primary tuning [55,61–63] TRPV4 Shear, osmotic, moderate stretch Fluid-exposed, volume-regulating Sustains/amplifies Ca 2+ , fine-tuning [55,62] TRPC5 Stretch, pressure Select cell types Additional tuning, context-specific [64] 4. The HAS2–Calcium Signaling Cascade: Molecular Mechanisms 4.1. From Mechanical Force to HAS2 Transcription Mechanical forces initiate a multi-step cascade that translates physical stimuli into HAS2 gene activation. First, mechanosensitive Ca 2+ channels detect tissue deformation and generate initial Ca 2+ influx. This primary signal is then amplified through a secondary mechanism: when cells sense mechanical force through their structural connections to the surrounding matrix, integrins cluster at focal adhesion sites and activate focal adhesion kinase (FAK), Src family kinases, and phospholipase C [ 47 ]. These molecules trigger Ca 2+ release from internal storage compartments (the endoplasmic reticulum) through IP 3 https://doi.org/10.3390/ijms27010160 Int. J. Mol. Sci. 2026,27, 160 7 of 19 receptor activation, providing a secondary, amplified Ca 2+ wave that complements the initial influx from stretch-activated channels [65]. This combined Ca 2+ signal must then be translated into genetic instructions that activate HAS2 synthesis. The pathway from Ca 2+ elevation to HAS2 gene expression involves multiple signaling intermediates and transcription factors—including CaMKII, PKC, MAPK pathways, and CREB—that work sequentially to amplify the signal while providing multiple points for regulation and integration with other pathways (detailed in Section 4.2). Studies in keratinocytes have provided the most detailed characterization of this cascade [ 45 ], though evidence shows it is a broadly conserved mechanism found in neurons, epithelial, and other cell types [66,67]. Mechanical load changes trigger Ca2+ elevation, which drives HAS2 upregulation, leading to increased HA synthesis and enhanced tissue hydration and gliding capacity. This coupling allows for continued movement, which closes the loop. 4.2. The Molecular Relay: CaMKII, PKC, MAPK, and CRE 4.2.1. Signal Amplification: The Molecular Megaphone Signal amplification in cellular signaling is a process of molecular multiplication, in which each kinase acts as a molecular megaphone, activating multiple downstream targets simultaneously. Ca 2+ signaling integrates with other pathways involving YES kinase and hyaluronan (HA) receptors such as CD44 and RHAMM to modulate HAS2 expression and extracellular matrix remodeling. These interactions provide additional regulatory layers beyond Ca 2+ -dependent kinases and transcription factors, allowing cross-talk that finetunes HAS2 gene activation and cellular responses [ 68 ]. Growth factors like FGF9 further promote HAS2 expression through activation of the Wnt/ β -catenin/TCF7L2 pathway, a critical signaling axis involved in development, tissue homeostasis, and disease [69,70]. The Wnt/ β -catenin pathway regulates gene transcription by stabilizing β -catenin, which partners with TCF/LEF transcription factors. The pathway drives target gene expression, including HAS2, linking extracellular signals to genetic programs [ 68 , 69 ]. Convergence of Ca 2+ signaling with YES kinase, HA receptor pathways, and Wnt/ β -catenin signaling highlights a complex network where multiple inputs integrate to control HAS2 expression and extracellular matrix dynamics. Such multi-pathway integration ensures precise regulation of HAS2 in response to diverse physiological and pathological stimuli. This cascading mechanism allows a small initial signal—in this case, a brief Ca 2+ influx—to generate a robust cellular response by progressively increasing its strength and range. The multi-step pathway not only amplifies the signal but also provides critical regulatory checkpoints, enabling the cell to fine-tune its response to different magnitudes and durations of mechanical stimulation, ultimately translating mechanical force into precise genetic activation. 4.2.2. The Sequential Relay: CaMKII →PKC →MAPK →CREB The first major responder is Ca 2+ /calmodulin-dependent protein kinase II (CaMKII). This serine/threonine kinase is directly activated when Ca 2+ binds to calmodulin, thereby switching on CaMKII’s enzymatic activity. Even after the Ca 2+ signal fades and returns to baseline levels, CaMKII can remain active for minutes or even hours, allowing brief Ca 2+ spikes to generate lasting cellular changes [ 37 , 67 ] (Table 3). Simultaneously, multiple isoforms of protein kinase C (PKC) become activated in response to both elevated Ca 2+ and diacylglycerol (DAG), which is produced alongside IP 3 when phospholipase C splits membrane lipids, and once activated, PKC begins phosphorylating components of the MAPK cascade, creating a critical connection that links the initial Ca 2+ signal to a major cellular communication highway [37]. https://doi.org/10.3390/ijms27010160 Int. J. Mol. Sci. 2026,27, 160 8 of 19 Table 3. CaMKII—From Ca 2+ Signal to Lasting Cellular Change. CaMKII’s role in converting Ca 2+ signals into persistent cellular and tissue changes. Step Description/Outcome Citations Ca2+ binds calmodulin Activates CaMKII [71–73] CaMKII autophosphorylation Maintains activity after Ca2+ returns to baseline [71–74] Downstream phosphorylation Modifies gene expression, cytoskeleton, tissue behavior [72–74] Structural integration 12-mer holoenzyme, supports elastic network adaptation [72–74] The mitogen-activated protein kinase (MAPK) pathways—particularly ERK1/2, p38, and JNK—act as the middle segment of this relay, passing the signal along by phosphorylating transcription factors that can enter the cell nucleus and bind directly to DNA, with ERK1/2 showing particularly strong involvement in activating HAS2 expression [ 37 ]. The final critical player is CREB (cAMP response element-binding protein), a transcription factor that receives phosphate modifications from multiple kinases, including both the MAPK cascade and CaMKII. Once phosphorylated and activated, this “master switch” binds to specific DNA sequences called cAMP response elements (CREs) in the HAS2 gene’s promoter region, recruiting additional coactivators that work together to initiate transcription and produce messenger RNA that will ultimately be translated into HAS2 enzyme protein [37]. 4.2.3. Temporal Dynamics of the Cascade The cascade unfolds according to a precise temporal schedule: initial Ca 2+ elevation occurs within seconds of stimulus application, activation of intermediate kinases follows within minutes, HAS2 mRNA levels begin to increase within 1–2 h and peak at 4–6 h poststimulation, and newly synthesized HA accumulates in the pericellular and extracellular space over the subsequent hours, with maximal accumulation typically observed 6–12 h after the initial stimulus [ 37 ]. We argue that this represents a temporal cascade allowing fascia to detect mechanical challenges almost instantly while mounting a sustained adaptive response over hours. This bridges the critical gap between immediate sensing and meaningful tissue-level change. 5. HA Extrusion: Simultaneous Synthesis and Secretion 5.1. HAS2: Both a Synthase and a Translocator HAS2 functions like a biological 3D printer, building the HA polymer chain on one side of the cell membrane while simultaneously threading it through to the other side, manufacturing and delivering the product in a single continuous process. As a Class I membrane-integrated enzyme, HAS2 uses a processive chain elongation mechanism, catalyzing the alternating addition of UDP-activated sugars (UDP-glucuronic acid and UDP-N-acetylglucosamine) to the growing HA chain while channeling the polymer through a transmembrane pore directly into the extracellular space [75]. This integration of a cytosolic catalytic domain with a channel-forming transmembrane region allows HAS2 to couple HA polymerization with secretion efficiently. Posttranslational modifications such as O-GlcNAcylation stabilize HAS2 in the membrane and enhance HA production, whereas phosphorylation by AMPK can inhibit HA secretion, linking HA extrusion to cellular energy status [ 76 ]. Increased HAS2 expression or activity leads to elevated HA synthesis and extrusion, which can promote pathological remodeling processes, such as in pulmonary hypertension and cancer [ 77 – 79 ]. Thus, HAS2 functions https://doi.org/10.3390/ijms27010160 Int. J. Mol. Sci. 2026,27, 160 9 of 19 as both a synthase and a translocator, producing and extruding HA directly into the ECM through its membrane-embedded structure. 5.2. Negative Feedback and Signal Termination Mechanisms for Termination The elegant responsiveness of the Ca 2+ -HA loop and its ability to detect mechanical stress and rapidly mobilize adaptive responses through the calmodulin–CaMKII cascade carries an inherent danger. Any signaling system capable of rapid, amplified responses must also possess mechanisms for termination, or it risks runaway activation that could damage rather than protect tissue. Uncontrolled Ca 2+ signaling leads to excitotoxicity, cellular dysfunction, and ultimately cell death. Specifically, unchecked HAS2 activation and excessive HA synthesis can create pathological tissue states (see Table 4). HA’s strong hydrophilic nature means that excessive production leads to pathological water retention and tissue edema, particularly in inflamed or injured tissues [ 71 , 72 ]. Conversely, dense, overly viscous HA-rich matrices impede normal cellular migration, affecting tissue repair and immune responses—the very processes that appropriate HA synthesis should facilitate [72–74,80]. Table 4. Pathological consequences of unchecked HAS2 activation and excessive HA synthesis. Pathological State Mechanism/Consequence Citations Edema (Water Retention) HA’s strong hydrophilic nature leads to water retention and tissue swelling [80,81] Impaired Cell Migration Overly viscous HA-rich matrices hinder cell movement and tissue repair [77,79,81,82] Progressive Fibrosis Excess HA promotes activation of fibroblasts/myofibroblasts, ECM deposition, and scarring [77,79,83,84] Tumor Progression HA-rich stroma supports cancer cell invasion, immune evasion, and metastasis [16,78,79,82] Perhaps most concerning, excessive HAS2-driven HA synthesis promotes progressive fibrosis through activation of fibroblasts and myofibroblasts, leading to pathological ECM deposition and tissue scarring in liver, kidney, and lung tissues [ 73 , 74 , 79 , 81 ]. In pathological contexts such as cancer, high HAS2/HA levels create a fibrotic, immunosuppressive microenvironment that supports tumor progression and therapeutic resistance [ 73 , 77 , 80 , 82 ]. 6. HA–Receptor Signaling 6.1. CD and RHAMM Oscillation Powers the CHA Feedback Loop Once extruded, the HA accumulates in the pericellular matrix and binds to its primary receptors, CD44 and RHAMM (Receptor for Hyaluronan-Mediated Motility), on the cell surface (see Figure 4). CD44 and RHAMM are mechanotransducers that convert HA binding into ion flux, cytoskeletal change, and gene expression. CD44 engages with highmolecular-weight HA (HMW-HA), which triggers multiple signaling pathways, including those involving Src family kinases, Rho GTPases, and PI3K/Akt, regulating cell adhesion, migration, and gene expression [ 79 , 85 , 86 ]. RHAMM engagement with low-molecularweight HA (LMW-HA) activates ERK/MAPK and FAK pathways that promote cell motility and tissue remodeling [ 87 ]. 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