Mechanical regulation of bone remodeling.
Wang L
Bone remodeling is a lifelong process that gives rise to a mature, dynamic bone structure via a balance between bone formation by osteoblasts and resorption by osteoclasts. These opposite processes allow the accommodation of bones to dynamic mechanical forces, altering bone mass in response to changing conditions. Mechanical forces are indispensable for bone homeostasis; skeletal formation, resorption, and adaptation are dependent on mechanical signals, and loss of mechanical stimulation can therefore significantly weaken the bone structure, causing disuse osteoporosis and increasing the risk of fracture. The exact mechanisms by which the body senses and transduces mechanical forces to regulate bone remodeling have long been an active area of study among researchers and clinicians. Such research will lead to a deeper understanding of bone disorders and identify new strategies for skeletal rejuvenation. Here, we will discuss the mechanical properties, mechanosensitive cell populations, and mechanotransducive signaling pathways of the skeletal system.
Human mesenchymal stem cells (hMSCs), for instance, can be readily switched from adipogenesis to osteogenesis simply by changing the matrix stiffness (Das, R. K., Stressstiffening-mediated stem-cell commitment switch in soft responsive hydrogels. Nat. Mater. 15, 318–325. 2016). The intensity and type of workout may lead to different results. Proper exercise can increase bone mass, while increasing exercise intensity to excessive levels can diminish bone mass and quality and even cause increased stress fractures.
Effects of mechanical stress stimulation on function and expression mechanism of osteoblasts.
Pan Liu.
Mechanical forces affect almost every sphere of various life processes of living organisms, such as the perception of external hearing and touch, fluid flow and deformation during embryonic development, changes in cell osmotic pressure, pressure on blood vessel walls, and the movement of individual animals regulated by the earth’s gravitational environment. These forces range from mechanical stress signal generation, induction, and transduction to the final response, which involves the cell membrane, cytoderm, cytoskeleton, and other structures.
Bone tissue is very sensitive to mechanical stress stimulation. Unloading and loading of mechanical stress are closely involved in the differentiation and formation of osteoclasts and osteoblasts, and their bone resorption and formation functions, respectively (Robling and Turner, 2009; Li et al., 2020a). Consequently, mechanical stress exerts an important influence on the bone microenvironment and metabolism. Wolff’s Law points out that the lack of mechanical stress would lead to bone microstructure degeneration, mass loss and metabolism disorders, and would ultimately lead to osteoporosis (Brand, 2010). The absence of mechanical stress, such as with limb casts fixation, bed-rest, reduced exercise, and the weightlessness of astronauts in space, can lead to significant bone loss (Berg et al., 2007; Ragnarsson, 2015). In contrast, the mechanical load caused by exercise can restore bone mass and reverse these effects in most situations (Iura et al., 2015; Suniaga et al., 2018).
Exposure of tissues and cells to external mechanical stress transforms the external mechanical force into local mechanical signals in the body, triggering responses of cellular sensors. Subsequently, cellular mechanical signals are coupled to biochemical signaling molecules such as the nitric oxide produced and prostaglandins (PGs) (Duncan and Turner, 1995; Johnson et al., 1996; Klein-Nulend et al., 1997). Osteoblasts, osteocytes, bone lining cells, osteoclasts, and macrophages can sense mechanical stimulation and respond directly or indirectly (Dong et al., 2021). Mechanical transduction in bone tissue cells is a complex but precise regulatory process between cells and the microenvironment, between adjacent cells, and between mechanical sensors with different functions in a single cell. Ion channels, integrins, gap junction proteins, focal adhesion kinase, the extracellular matrix, the cellular skeletal components (such as intermediate filaments, microtubules, and actin filaments), and primary cilia are mechanical sensors that have been proven to regulate intracellular signaling pathways (Qin et al., 2020).
Loading and unloading mechanical stress affects the proliferation, differentiation, and function of osteoblast-like cells. Studies have shown that osteoblast-like cells, which are sensitive to mechanical stimulation, are the basic cell model for studying the processes of bone growth, development, and formation (Siddiqui and Partridge, 2016; Thomas and Jaganathan, 2021). The perception of mechanical stress by osteoblasts first involves actions on target genes through various pathways such as Ca2+, Piezo1, ECM-integrin-cytoskeleton, and cell regulatory factors. Mechanoreceptor also regulates the expression of corresponding genes to convert mechanical stimulus signals to chemical stimuli, and then regulates various receptors on the cell membrane, cytoplasm, and nucleus through chemoreceptors to regulate the bone formation mechanism (Steward and Kelly, 2015; Augat et al., 2021). Mechanical stimulation is an important regulatory factor for bone growth, reconstruction, and metabolism. Number experimental studies have investigated osteogenic effects under mechanical stress (Chermside-Scabbo et al., 2020; Eichholz et al., 2020; Jeon et al., 2021; Lei et al., 2021). The influence of different mechanical forces on bone tissue produces various effects. Analyzing the mechanism mediating the effects of mechanical stimulation on the regulation and metabolism of cell signaling pathways such as those of BMSCs, osteoblasts, osteoclasts, and osteocytes is currently a challenging research hotspot. Most previous studies used a single mechanical stimulus on a single mechanosensitive cell, and the mechanical loading methods and mechanical devices used did not have a relatively unified standard.
The results obtained from studies using randomly selected or combinations of different mechanical stimuli were no systematic and lacked standardization and accuracy. Consequently, designs of bone metabolism studies need to include a more suitable mechanical experimental environment to accurately control the mechanical parameters of mechanical stress stimulation, such as the type, duration, intensity, and cycle of mechanical stimulation). Furthermore, such studies should explore the influence of the body on mechanical stimulation. These results could be used as a foundation for future orthopedics, stomatology, and tissue engineering research studies to advance the development of this discipline.
Mechanotransduction: Tuning Stem Cells Fate
D’Angelo F.
Abstract: It is a general concern that the success of regenerative medicine-based applications is based on the ability to recapitulate the molecular events that allow stem cells to repair the damaged tissue/organ. To this end biomaterials are designed to display properties that, in a precise and physiological-like fashion, could drive stem cell fate both in vitro and in vivo. The rationale is that stem cells are highly sensitive to forces and that they may convert mechanical stimuli into a chemical response. In this review, we describe novelties on stem cells and biomaterials interactions with more focus on the implication of the mechanical stimulation named mechanotransduction. Mechanical forces (e.g., gravity, tension, compression, hydrostatic pressure, and fluid shear stress) influence the growth and shape of every tissue and organ under physiological and pathological conditions. Additionally, traction forces generated by cells may markedly influence many biological processes such as self-renewal and differentiation. Research is focused on the identification of critical mechanosensitive molecules and cellular components that contribute to the mechanotransduction response. The presence of isometric tension (prestress) at all levels of these multiscale networks ensures that various molecular scale mechanochemical transduction mechanisms proceed simultaneously and produce a concerted response. Future research in this area will therefore require a better understanding of tensionally integrated (tensegrity) systems of mechanochemical controls. Highly coordinated extensive cellular components including cytoskeleton, adhesion complexes, and ion channels have been implicated as the primary mediators of mechanotransduction suggesting that, the generation of successful tissue engineering implants depend on the control of mechanical forces. For instance, it has been demonstrated that nanoscale topographies were able to stimulate human MSCs to produce bone mineral in vitro, in the absence of osteogenic supplements, and with efficiency comparable to that of cells cultured with osteogenic media. Moreover, a recent advance made in the tissue engineering field is the generation of selective differentiation of MSCs into specific cells phenotype by applying various mechanical forces using matrix stiffness or topography.
Stem cells respond to different mechanical forces loading by activating multiple intracellular signaling pathways that are implicated in the maintenance and regulation of cellular functions. Stem cells can sense the mechanical loading through a diverse group of membrane-anchored mechanosensors (stretch-activated ion channels, cell-membrane-spanning G-protein-coupled receptors, and integrins). This mechanical stimulus is then converted to biochemical signals by triggering the multi-step activation of downstream partners in an array of signaling cascades in the cytoplasm.
In conclusion, the future of regenerative medicine is based on the fabrication of innovative devices that take into account the feedback between stem cells biology, cell sensing of force, and biomaterials‟ properties (topography, stiffness, electrical conductibility, drugs release and form).
Insight into Mechanobiology: How Stem Cells Feel Mechanical Forces and Orchestrate Biological Functions.
Argentati C.
Mechanosensing
All organisms have evolved structures, enabling them to recognize and respond to mechanical forces. This cross-talk takes place at the macroscale level (e.g., in organs and tissues), at the microscale level(e.g., in single cells), and also at the nanoscale level(e.g., inmolecular complexes or single proteins). At present, we know that the different types of forces orchestrate the control of all biological functions, including stem cells’ commitment, determination, development, and maintenance of cells and tissues homeostasis.
Notably, between ECM and stem cells exists a dynamic cross-talk, as stem cells may change the ECM composition and remodel the architecture either by the secretion of ECM structural components and matrix metalloproteinases, or by exerting mechanical forces through the cytoskeleton f ibers. The challenge is to create a suitable cell microenvironment that generates mechanosensing/ mechanotransduction signals and guide stem cells’ functions.
The rationale of the use of biomaterials as stem cells support is based on the cross-talk taking place between them. Stem cells act on biomaterials releasing ECM proteins and bioactive molecules and exert forces through the cytoskeletal components to recreate their niche. Conversely, biomaterials act on stem cells through their intrinsic chemical-physical properties, which activate mechanosensing/mechano- transduction signalling and thereby modulate the stem cells fate. Different types of natural (e.g., collagen, fibrin, silk) and synthetic (e.g., polylactic acid, polyamide, polyesters, polyanhydrides, polyurethane) polymers have been manipulated to fabricate biocompatible films (two-dimensional) or scaffolds (three-dimensional) with tuneable properties to guide stem cells fate.
Mechanical cues activated by the ECM and translated to the cell through mechanosensing/mechano- transduction signals represent a general scheme by which cells, tissues, organs, and whole organisms respond to external mechanical stimuli orchestrating their biologic activity.
Advances in the use of biomaterials as support for in vitro stem cells cultures to generate ex-vivo models of tissues and organs, together with computational systems, have highlighted the potentials of mechanobiology as a new therapeutic tool to be investigated for RM applications.
Effect of hydrostatic pressure on bone regeneration using human mesenchymal stem cell
Huang C.
Mechanics is increasingly being recognized as the fourth essential factor in bone tissue engineering next to cell, scaffold, and growth factors. The development of bioprocessors has made it possible to simulate the in vivo mechanics that are needed to generate three-dimensional (3D) bone constructs. However, although hydrostatic pressure (HP) is a dominant and constant mechanical strain on bone cells in vivo, little is known about the effect of HP applied via perfusion bioprocessors on in vitro human bone marrow-derived mesenchymal stem cell (hMSC) behavior
Influence of mechanical forces on cells and tissues.
Stoltz J.F.
All cells and tissues of the organism are continually subject to mechanical stresses. These forces have many various origins, from pressure forces linked to gravity to motion forces (i.e., blood circulation, loading on cartilage and bone during walking,....). Their range is a few Pascals in vascular wall shear stress and several mega-Pascals in hip cartilage (1,2,3). It has now been accepted that these applied forces are likely to modify cellular behaviour by affecting metabolism, paracrine or autocrine factor secretion and gene expression.
While research in biorheology and biomechanics have in the last decades helped understanding the physical properties of cells and tissues, recent works have focussed on the physiological consequences of applied stresses and opened a new avenue for research that can be defined as “mechanobiology”, leading through its applications to a better understanding of a variety of diseases or pathological conditions (cardiovascular, inflammation, arthrosis, etc….) and to novel therapeutical approaches using tissue engineering concept and the development of a new generation of biomaterials (biotissues).
As most cells and tissues in the organism are interested by these new approaches, certain cells have drawn researchers’ attention even more because of their clinical significance, such is the case for chondrocytes, bone cells, smooth muscle cells and vascular endothelial cells. However, although the physiological effects of stress are now well known, the various steps leading from the mechanical signal to physiological response and gene expression have yet to be clarified.
