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Multiple myeloma bone disease (MMBD) is characterized by the growth of malignant plasma cells in bone marrow, leading to an imbalance in bone (re)modeling favoring excessive resorption. Loss of bone mass and altered microstructure characterize MMBD in humans and preclinical animal models, although, no study to date has examined bone composition or material properties. We hypothesized that MMBD alters bone composition, mineral crystal properties and mechanical properties in the MOPC315.BM.Luc model after intra-tibial injection of myeloma cells and three weeks of daily in vivo tibial loading. Decreased cortical bone elastic modulus and hardness measured by nanoindentation of tibiae were observed in MM-injected mice compared to PBS-injected mice, whereas cortical bone composition, mineral crystal properties measured by Fourier-transform infrared imaging or small angle X-ray scattering, respectively remained unchanged. However, MM-injected mice had thinner cancellous bone mineral particles compared to PBS-injected mice. Mechanical loading did not lead to altered cortical bone composition, mineral structure, or mechanical properties in the context of MM. Unexpectedly, we observed the intra-tibial injection itself altered the material composition of bone, manifested by increased matrix mineralization and crystal size of the hydroxyapatite crystals in the bone matrix. In conclusion, our data suggest that mechanical stimuli can be used as an adjuvant bone anabolic therapy in patients with MMBD to rebuild bone with unaltered composition and mineral structure to reduce subsequent fracture risk.

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We and others have shown that application of high-level mechanical loading promotes the formation of transient plasma membrane disruptions (PMD) which initiate mechanotransduction. We hypothesized that increasing osteocyte cell membrane fragility, by disrupting the cytoskeleton-associated protein ß2-spectrin (Sptbn1), could alter osteocytic responses and bone adaptation to loading in a PMD-related fashion. In MLO-Y4 cells, treatment with the spectrin-disrupting agent diamide or knockdown of Sptbn1 via siRNA increased the number of PMD formed by fluid shear stress. Primary osteocytes from an osteocyte-targeted DMP1-Cre Sptbn1 conditional knockout (CKO) model mimicked trends seen with diamide and siRNA treatment and suggested the creation of larger PMD, which repaired more slowly, for a given level of stimulus. Post-wounding cell survival was impaired in all three models, and calcium signaling responses from the wounded osteocyte were mildly altered in Sptbn1 CKO cultures. Although Sptbn1 CKO mice did not demonstrate an altered skeletal phenotype as compared to WT littermates under baseline conditions, they showed a blunted increase in cortical thickness when subjected to an osteogenic tibial loading protocol as well as evidence of increased osteocyte death (increased lacunar vacancy) in the loaded limb after 2 weeks of loading. The impaired post-wounding cell viability and impaired bone adaptation seen with Sptbn1 disruption support the existence of an important role for Sptbn1, and PMD formation, in osteocyte mechanotransduction and bone adaptation to mechanical loading.

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It is not clear as to whether weight bearing and ambulation may affect bone growth. Our goal was to study the role of mechanical loading (one of the components of ambulation) on endochondral ossification and longitudinal bone growth. Thus, we applied cyclical, biologically relevant strains for a prolonged time period (4 weeks) to one tibia of juvenile mice, while using the contralateral one as an internal control. By the end of the 4-week loading period, the mean tibial growth of the loaded tibiae was significantly greater than that of the unloaded tibiae. The mean height and the mean area of the loaded tibial growth plates were greater than those of the unloaded tibiae. In addition, in female mice we found a greater expression of PTHrP in the loaded tibial growth plates than in the unloaded ones. Lastly, microCT analysis revealed no difference between loaded and unloaded tibiae with respect to the fraction of bone volume relative to the total volume of the region of interest or the tibial trabecular bone volume. Thus, our findings suggest that intermittent compressive forces applied on tibiae at mild-moderate strain magnitude induce a significant and persistent longitudinal bone growth. PTHrP expressed in the growth plate appears to be one growth factor responsible for stimulating endochondral ossification and bone growth in female mice.

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Skeletal muscle adaptation to exercise involves various phenotypic changes that enhance the metabolic and contractile functions. One key regulator of these adaptive responses is the activation of AMPK, which is influenced by exercise intensity. However, the mechanistic understanding of AMPK activation during exercise remains incomplete. In this study, we utilized an in vitro model to investigate the effects of mechanical loading on AMPK activation and its interaction with the mTOR signaling pathway. Proteomic analysis of muscle cells subjected to static loading (SL) revealed distinct quantitative protein alterations associated with RNA metabolism, with 10% SL inducing the most pronounced response compared to lower intensities of 5% and 2% as well as the control. Additionally, 10% SL suppressed RNA and protein synthesis while activating AMPK and inhibiting the mTOR pathway. We also found that SRSF2, necessary for pre-mRNA splicing, is regulated by AMPK and mTOR signaling, which, in turn, is regulated in an intensity-dependent manner by SL with the highest expression in 2% SL. Further examination showed that the ADP/ATP ratio was increased after 10% SL compared to the control and that SL induced changes in mitochondrial biogenesis. Furthermore, Seahorse assay results indicate that 10% SL enhances mitochondrial respiration. These findings provide novel insights into the cellular responses to mechanical loading and shed light on the intricate AMPK-mTOR regulatory network in muscle cells.

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The importance of mechanical loading and its relationship to orthobiologic therapies in the treatment of post-traumatic osteoarthritis (PTOA) is beginning to receive attention. This review explores the current efficacy of orthobiologic interventions, notably platelet-rich plasma (PRP), bone marrow aspirate (BMA), and mesenchymal stem/stromal cells (MSCs), in combating PTOA drawing from a comprehensive review of both preclinical animal models and human clinical studies. This review suggests why mechanical joint loading, such as running, might improve outcomes in PTOA management in conjunction with orthiobiologic administration. Accumulating evidence underscores the influence of mechanical loading on chondrocyte behavior and its pivotal role in PTOA pathogenesis. Dynamic loading has been identified as a key factor for optimal articular cartilage (AC) health and function, offering the potential to slow down or even reverse PTOA progression. We hypothesize that integrating the activation of mechanotransduction pathways with orthobiologic treatment strategies may hold a key to mitigating or even preventing PTOA development. Specific loading patterns incorporating exercise and physical activity for optimal joint health remain to be defined, particularly in the clinical setting following joint trauma.

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The primary aim of this study was to explore the effects of team sports practice on bone health indices in adults engaged in team sports. The secondary aim was to investigate the osteogenic effects of each type of team sport. This systematic literature search was conducted using common electronic databases from inception in June 2023, using key terms (and synonyms searched for by the MeSH database) that were combined using the operators "AND", "OR", "NOT": (``men'' OR ``man'' OR ``women'' OR ``woman'') AND (``bone mineral density'' OR ``BMD'' OR ``bone mineral content'' OR ``BMC'' OR ``peak bone mass'' OR ``mechanical loading'' OR ``osteoporosis'' OR ``bone geometry'' OR ``bone resistance'') AND (``team sport'' OR ``sport'' OR rugby OR basketball OR volleyball OR handball OR soccer OR football OR ``players''). After screening, 16 studies were included in the final analysis (5 continents, 2740 participants). The training duration lasted 1 to 13 years. Team sport training had a moderate impact on whole body bone mineral density (WB BMD) (1.07 SMD; 95 % [0.77, 1.37], p < 0.00) but a more significant impact on whole body bone mineral content (WB BMC) (1.3 SMD; 95 % [0.81, 1.79], p < 0.00). Subgroup analyses indicated that rugby training had a moderate but non-significant impact on WB BMD (1.19 SMD; 95 % [-0.13, 2.52], p = 0.08) but a greater impact on WB BMC (2.12 SMD; 95 % [0.84, 3.39], p < 0.00); basketball training had a moderate but significant impact on WB BMD (1 SMD; 95 % [0.35, 1.64], p < 0.00) and a trivial non-significant impact on WB BMC (0.18 SMD; 95 % [-1.09, 1.46], p = 0.78); volleyball training had a moderate but non-significant impact on WB BMD (0.63 SMD; 95 % [-0.22, 1.49], p = 0.15) and a significant impact on WB BMC (2.39 SMD; 95 % [1.45, 3.33], p < 0.00). Handball training produced a moderate significant impact on WB BMD (1.02 SMD; 95 % [0.33, 1.71], p < 0.00) and WB BMC (0.97 SMD; 95 % [0.47, 1.48], p < 0.00), and soccer training led to moderate but significant effects on WB BMD (1.16 SMD; 95 % [0.88, 1.44], p < 0.00) and a large effect on WB BMC (1.34 SMD; 95 % [0.92, 1.77], p < 0.00). Rugby training was associated with a higher WB BMC compared to basketball training (p = 0.03). Our systematic review and meta-analysis suggests that team sports, such as rugby, basketball, volleyball, handball and soccer have moderate to large effects on WB BMD and WB BMC. Specifically, our findings indicate that handball and soccer enhance WB BMD and WB BMC, whereas rugby only increases WB BMC. There is currently insufficient evidence indicating the superiority of any type of sport training that improves bone health in adults.

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In response to mechanical loading of bone, osteocytes produce nitric oxide (NO•) and decrease sclerostin protein expression, leading to an increase in bone mass. However, it is unclear whether NO• production and sclerostin protein loss are mechanistically linked, and, if so, the nature of their hierarchical relationship within an established mechano-transduction pathway. Prior work showed that following fluid-shear stress (FSS), osteocytes produce NOX2-derived reactive oxygen species, inducing calcium (Ca2+) influx. Increased intracellular Ca2+ results in calcium-calmodulin dependent protein kinase II (CaMKII) activation, which regulates the lysosomal degradation of sclerostin protein. Here, we extend our discoveries, identifying NO• as a regulator of sclerostin degradation downstream of mechano-activated CaMKII. Pharmacological inhibition of nitric oxide synthase (NOS) activity in Ocy454 osteocyte-like cells prevented FSS-induced sclerostin protein loss. Conversely, short-term treatment with a NO• donor in Ocy454 cells or isolated murine long bones was sufficient to induce the rapid decrease in sclerostin protein abundance, independent of changes in Sost gene expression. Ocy454 cells express all three NOS genes, and transfection with siRNAs targeting eNOS/Nos3 was sufficient to prevent FSS-induced loss of sclerostin protein, while siRNAs targeting iNOS/Nos2 mildly blunted the loss of sclerostin but did not reach statistical significance. Similarly, siRNAs targeting both eNOS/Nos3 and iNOS/Nos2 prevented FSS-induced NO• production. Together, these data show iNOS/Nos2 and eNOS/Nos3 are the primary producers of FSS-dependent NO•, and that NO• is necessary and sufficient for sclerostin protein control. Further, selective inhibition of elements within this sclerostin-controlling mechano-transduction pathway indicated that NO• production occurs downstream of CaMKII activation. Targeting Camk2d and Camk2g with siRNA in Ocy454 cells prevented NO• production following FSS, indicating that CaMKII is needed for NO• production. However, NO• donation (1min) resulted in a significant increase in CaMKII activation, suggesting that NO• may have the ability to tune CaMKII response. Together, these data support that CaMKII is necessary for, and may be modulated by NO•, and that the interaction of these two signals is involved in the control of sclerostin protein abundance, consistent with a role in bone anabolic responses.

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BACKGROUND: Understanding how healthy articular cartilage responds to mechanical loading is critical. Moderate mechanical loading has positive effects on the cartilage, such as maintaining cartilage homeostasis. The degree of mechanical loading is determined by a combination of intensity, frequency, and duration; however, the best combination of these parameters for knee cartilage remains unclear. This study aimed to determine which combination of intensity, frequency, and duration provides the best mechanical loading on healthy knee articular cartilage in vitro and in vivo. METHODS AND RESULTS: In this study, 33 male mice were used. Chondrocytes isolated from mouse knee joints were subjected to different cyclic tensile strains (CTSs) and assessed by measuring the expression of cartilage matrix-related genes. Furthermore, the histological characteristics of mouse tibial cartilages were quantified using different treadmill exercises. Chondrocytes and mice were divided into the control group and eight intervention groups: high-intensity, high-frequency, and long-duration; high-intensity, high-frequency, and short-duration; high-intensity, low-frequency, and long-duration; high-intensity, low-frequency, and short-duration; low-intensity, high-frequency, and long-duration; low-intensity, high-frequency, and short-duration; low-intensity, low-frequency, and long-duration; low-intensity, low-frequency, and short-duration. In low-intensity CTSs, chondrocytes showed anabolic responses by altering the mRNA expression of COL2A1 in short durations and SOX9 in long durations. Furthermore, low-intensity, low-frequency, and long-duration treadmill exercises minimized chondrocyte hypertrophy and enhanced aggrecan synthesis in tibial cartilages. CONCLUSION: Low-intensity, low-frequency, and long-duration mechanical loading is the best combination for healthy knee cartilage to maintain homeostasis and activate anabolic responses. Our findings provide a significant scientific basis for exercise and lifestyle instructions.

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Traditional tendon engineering using cell-loaded scaffold has limited application potential due to the need of autologous cells. We hypothesize that potent mechanical loading can efficiently induce in situ Achilles tendon regeneration in a rabbit model by using a cell-free porous composite scaffold. In this study, melt-spinning was used to fabricate PGA (polyglycolic acid) and PLA (polylactic acid) filament fibers as well as non-woven PGA fibers. The PLA/PGA (4:2) filament fibers were further braided into a hybrid yarn，which was knitted into a PLA/PGA tubular mesh with potent mechanical property for sustaining natural tendon strain. The results showed that a complete cross-section of Achilles tendon created a model of full mechanical loading on the bridging scaffold, which could efficiently induce in situ tendon regeneration by promoting host cell infiltration, matrix production and tissue remodeling. Histologically, mechanical loading assisted in forming parallel aligned collagen fibers and tenocytes in a fashion similar to those of native tendon. Transmission electron microscope further demonstrated that mechanical strain induced collagen fibril development by increasing fibril diameter and forming bipolar structure, which resulted in enhanced mechanical properties. Interestingly, the synergistic effect between mechanical loading and hyaluronic acid modification was also observed on the induced tenogenic differentiation of infiltrated host fibroblasts. In conclusion, potent mechanical loading is the key inductive microenvironment for in situ tendon regeneration for this polymer-based composite scaffold with proper matrix modification, which may serve as a universal scaffold product for tendon regeneration.

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The musculoskeletal system, crucial for movement and support, relies on the delicate balance of connective tissue homeostasis. Maintaining this equilibrium is essential for tissue health and function. There has been increasing evidence in the past decade that shows the circadian clock as a master regulator of extracellular matrix (ECM) homeostasis in several connective tissue clocks. Very recently, exercise has emerged as a significant entrainment factor for cartilage and intervertebral disk circadian rhythms. Understanding the implications of exercise on connective tissue peripheral clocks holds promise for enhancing tissue health and disease prevention. Exercise-induced factors such as heat, glucocorticoid release, mechanical loading, and inter-tissue cross talk may play pivotal roles in entraining the circadian rhythm of connective tissues. This mini review underscores the importance of elucidating the mechanisms through which exercise influences circadian rhythms in connective tissues to optimize ECM homeostasis. Leveraging exercise as a modulator of circadian rhythms in connective tissues may offer novel therapeutic approaches to physical training for preventing musculoskeletal disorders and enhancing recovery.

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Introduction Fixed prosthodontic treatment involves the replacement of missing tooth structures with a variety of materials. Several newer metal-free ceramics have been developed in recent years to meet patients' aesthetic needs. The long-term performance of all ceramics, however, is unknown, necessitating a continuous evaluation of the materials' strength. Aim The aim of this study was to compare and evaluate the fracture resistance of IPS E max pressable crowns and graphene crowns, which are luted with Rely X U200 self-adhesive resin cement on the respective dies, as well as thermocycling of IPS E max pressable crowns and thermocycling of graphene crowns. The current review was conducted as an in vitro examination at the Division of Prosthodontics, GSL Dental School, Rajahmundry, Andhra Pradesh, India. Materials and methods On a typodont tooth, a shoulder finish line design was prepared and incisal reduction was performed. The tooth was scanned, designed, and milled to produce 18 metal dies made of cobalt-chrome alloy. These metal dies produced a total of (n=36) all-ceramic crowns, which were divided into two groups based on crown type: 18 IPS E max crowns and 18 graphene crowns. The participants were once again divided into two subgroups within each group, with the purpose of assessing fracture resistance. This evaluation was conducted using a universal testing machine both before and after subjecting the specimens to thermocycling. The obtained data were sent for statistical analysis. Results Fracture resistance values were reduced after thermocycling of both IPS E max and Graphene crowns. Without thermocycling, the fracture resistance values of IPS E max crowns were higher than those of graphene crowns. Conclusions The fracture resistance of IPS E max crowns exhibited a statistically significant increase when compared to graphene crowns. Additionally, it was shown that the fracture resistance of both materials was reduced upon exposure to thermocycling.

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OBJECTIVE: The present study aimed to investigate the underlying mechanism of mechanical stimulation in regulating osteogenic differentiation. MATERIALS AND METHODS: Osteoblasts were exposed to compressive force (0-4 g/cm2) for 1-3 days or CGRP for 1 or 3 days. Expression of receptor activity modifying protein 1 (RAMP1), the transcription factor RUNX2, osteocalcin, p38 and p-p38 were analyzed by western blotting. Calcium mineralization was analyzed by alizarin red straining. RESULTS: Using compressive force treatments, low magnitudes (1 and 2 g/cm2) of compressive force for 24 h promoted osteoblast differentiation and mineral deposition whereas higher magnitudes (3 and 4 g/cm2) did not produce osteogenic effect. Through western blot assay, we observed that the receptor activity-modifying protein 1 (RAMP1) expression was upregulated, and p38 mitogen-activated protein kinase (MAPK) was phosphorylated during low magnitudes compressive force-promoted osteoblast differentiation. Further investigation of a calcitonin gene-related peptide (CGRP) peptide incubation, a ligand for RAMP1, showed that CGRP at concentration of 25 and 50 ng/ml could increase expression levels of RUNX2 and osteocalcin, and percentage of mineralization, suggesting its osteogenic potential. In addition, with the same conditions, CGRP also significantly upregulated RAMP1 and phosphorylated p38 expression levels. Also, the combination of compressive forces (1 and 2 g/cm2) with 50 ng/ml CGRP trended to increase RAMP1 expression, p38 activity, and osteogenic marker RUNX2 levels, as well as percentage of mineralization compared to compressive force alone. This suggest that RAMP1 possibly acts as an upstream regulator of p38 signaling during osteogenic differentiation. CONCLUSION: These findings suggest that CGRP-RAMP1/p38MAPK signaling implicates in osteoblast differentiation in response to optimal magnitude of compressive force. This study helps to define the underlying mechanism of compressive stimulation and may also enhance the application of compressive stimulation or CGRP peptide as an alternative approach for accelerating tooth movement in orthodontic treatment.

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Many physical and chemical properties of solids, such as strength, plasticity, dispersibility, solubility and dissolution are determined by defects in the crystal structure. The aim of this work is to study in situ dynamic, dispersion, chemical, biological and surface properties of lacosamide powder after a complete cycle of mechanical loading by laser scattering, electron microscopy, FR-IR and biopharmaceutical approaches. The SLS method demonstrated the spontaneous tendency toward surface-energy reduction due to aggregation during micronisation. DLS analysis showed conformational changes of colloidal particles as supramolecular complexes depending on the loading time on the solid. SEM analysis demonstrated the conglomeration of needle-like lacosamide particles after 60 min of milling time and the transition to a glassy state with isotropy of properties by the end of the tribochemistry cycle. The following dynamic properties of lacosamide were established: elastic and plastic deformation boundaries, region of inhomogeneous deformation and fracture point. The ratio of dissolution-rate constants in water of samples before and after a full cycle of loading was 2.4. The lacosamide sample, which underwent a full cycle of mechanical loading, showed improved kinetics of API release via analysis of dissolution profiles in 0.1 M HCl medium. The observed activation-energy values of the cell-death biosensor process in aqueous solutions of the lacosamide samples before and after the complete tribochemical cycle were 207 kJmol-1 and 145 kJmol-1, respectively. The equilibrium time of dissolution and activation of cell-biosensor death corresponding to 20 min of mechanical loading on a solid was determined. The current study may have important practical significance for the transformation and management of the properties of drug substances in solid form and in solutions and for increasing the strength of drug matrices by pre-strain hardening via structural rearrangements during mechanical loading.

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Although mechanical loading is essential for maintaining bone health and combating osteoporosis, its practical application is limited to a large extent by the high variability in bone mechanoresponsiveness. Here, we found that gut microbial depletion promoted a significant reduction in skeletal adaptation to mechanical loading. Among experimental mice, we observed differences between those with high and low responses to exercise with respect to the gut microbial composition, in which the differential abundance of Lachnospiraceae contributed to the differences in bone mechanoresponsiveness. Microbial production of L-citrulline and its conversion into L-arginine were identified as key regulators of bone mechanoadaptation, and administration of these metabolites enhanced bone mechanoresponsiveness in normal, aged, and ovariectomized mice. Mechanistically, L-arginine-mediated enhancement of bone mechanoadaptation was primarily attributable to the activation of a nitric-oxide-calcium positive feedback loop in osteocytes. This study identifies a promising anti-osteoporotic strategy for maximizing mechanical loading-induced skeletal benefits via the microbiota-metabolite axis.

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Tendons are frequently injured and have limited regenerative capacity. This motivates tissue engineering efforts aimed at restoring tendon function through strategies to direct functional tendon formation. Generation of a crosslinked collagen matrix is paramount to forming mechanically functional tendon. However, it is unknown how lysyl oxidase (LOX), the primary mediator of enzymatic collagen crosslinking, is regulated by stem cells. This study investigates how multiple factors previously identified to promote tendon formation and healing (transforming growth factor [TGF]ß1 and TGFß2, mechanical stimuli, and hypoxia-inducible factor [HIF]-1α) regulate LOX production in the murine C3H10T1/2 mesenchymal stem cell (MSC) line. We hypothesized that TGFß signaling promotes LOX activity in C3H10T1/2 MSCs, which is regulated by both mechanical stimuli and HIF-1α activation. TGFß1 and TGFß2 increased LOX levels as a function of concentration and time. Inhibiting the TGFß type I receptor (TGFßRI) decreased TGFß2-induced LOX production by C3H10T1/2 MSCs. Low (5 mPa) and high (150 mPa) magnitudes of fluid shear stress were applied to test impacts of mechanical stimuli, but without TGFß2, loading alone did not alter LOX levels. Low loading (5 mPa) with TGFß2 increased LOX at 7 days greater than TGFß2 treatment alone. Neither HIF-1α knockdown (siRNA) nor activation (CoCl2) affected LOX levels. Ultimately, results suggest that TGFß2 and appropriate loading magnitudes contribute to LOX production by C3H10T1/2 MSCs. Potential application of these findings includes treatment with TGFß2 and appropriate mechanical stimuli to modulate LOX production by stem cells to ultimately control collagen matrix stiffening and support functional tendon formation.

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Prosthetic technology has advanced with the development of powered prostheses to enhance joint function and movement in the absence of native anatomy. However, there are no powered solutions available for hip-level amputees, and most existing hip prostheses are mounted to the front of the prosthetic socket, thereby limiting range of motion. This research introduces a novel laterally mounted powered hip joint (LMPHJ) that augments user movement. The LMPHJ is mounted on the lateral side of the prosthetic socket, positioning the hip joint closer to the anatomical center of rotation while ensuring user safety and stability. The motor and electronics are located in the thigh area, maintaining a low profile while transmitting the required hip moment to the mechanical joint center of rotation. A prototype was designed and manufactured, and static testing was complete by modifying the loading conditions defined in the ISO 15032:2000 standard to failure test levels for a 100 kg person, demonstrating the joint's ability to withstand everyday loading conditions. Functional testing was conducted using a prosthesis simulator that enabled able-bodied participants to successfully walk with the powered prosthesis on level ground. This validates the mechanical design for walking and indicates the LMPHJ is ready for evaluation in the next phase with hip disarticulation amputee participants.

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BACKGROUND: Osteoarthritis (OA) is a complex, age-related multifactorial degenerative disease of diarthrodial joints marked by impaired mobility, joint stiffness, pain, and a significant decrease in quality of life. Among other risk factors, such as genetics and age, hyper-physiological mechanical cues are known to play a critical role in the onset and progression of the disease (Guilak in Best Pract Res Clin Rheumatol 25:815-823, 2011). It has been shown that post-mitotic cells, such as articular chondrocytes, heavily rely on methylation at CpG sites to adapt to environmental cues and maintain phenotypic plasticity. However, these long-lasting adaptations may eventually have a negative impact on cellular performance. We hypothesize that hyper-physiologic mechanical loading leads to the accumulation of altered epigenetic markers in articular chondrocytes, resulting in a loss of the tightly regulated balance of gene expression that leads to a dysregulated state characteristic of the OA disease state. RESULTS: We showed that hyper-physiological loading evokes consistent changes in CpGs associated with expression changes (ML-tCpGs) in ITGA5, CAV1, and CD44, among other genes, which together act in pathways such as anatomical structure morphogenesis (GO:0009653) and response to wound healing (GO:0042060). Moreover, by comparing the ML-tCpGs and their associated pathways to tCpGs in OA pathophysiology (OA-tCpGs), we observed a modest but particular interconnected overlap with notable genes such as CD44 and ITGA5. These genes could indeed represent lasting detrimental changes to the phenotypic state of chondrocytes due to mechanical perturbations that occurred earlier in life. The latter is further suggested by the association between methylation levels of ML-tCpGs mapped to CD44 and OA severity. CONCLUSION: Our findings confirm that hyper-physiological mechanical cues evoke changes to the methylome-wide landscape of chondrocytes, concomitant with detrimental changes in positional gene expression levels (ML-tCpGs). Since CAV1, ITGA5, and CD44 are subject to such changes and are central and overlapping with OA-tCpGs of primary chondrocytes, we propose that accumulation of hyper-physiological mechanical cues can evoke long-lasting, detrimental changes in set points of gene expression that influence the phenotypic healthy state of chondrocytes. Future studies are necessary to confirm this hypothesis.

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Various mechanical loadings, including mechanical stress, orthodontics forces, and masticatory force, affect the functions of periodontal ligament cells. Regulation of periodontal tissue destruction, formation, and differentiation functions are crucial processes for periodontal regeneration therapy. Numerous studies have reported that different types of mechanical loading play a role in maintaining periodontal tissue matrix homeostasis, and osteogenic differentiation of the periodontal ligament cells. This scoping review aims to evaluate the studies regarding the effects of various mechanical loadings on the secretion of extracellular matrix (ECM) components, regulation of the balance between formation and destruction of periodontal tissue matrix, osteogenic differentiation, and multiple differentiation functions of the periodontal ligament. An electronic search for this review has been conducted on two databases; MEDLINE via PubMed and SCOPUS. Study selection criteria included original research written in English that reported the effects of different mechanical loadings on matrix homeostasis and differentiation potential of periodontal ligament cells. The final 204 articles were mainly included in the present scoping review. Mechanical forces of the appropriate magnitude, duration, and pattern have a positive influence on the secretion of ECM components such as collagen, as well as regulate the secretion of matrix metalloproteinases and tissue inhibitors of matrix metalloproteinases. Additionally, these forces regulate a balance between osteoblastic and osteoclast differentiation. Conversely, incorrect mechanical loadings can lead to abnormal formation and destruction of both soft and hard tissue. This review provides additional insight into how mechanical loadings impact ECM homeostasis and multiple differentiation functions of periodontal ligament cells (PDLCs), thus making it valuable for regenerative periodontal treatment. In combination with advancing technologies, the utilization of ECM components, application of different aspects of mechanical force, and differentiation potential of PDLCs could bring potential benefits to future periodontal regeneration therapy.

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Bone secretory proteins, termed osteokines, regulate bone metabolism and whole-body homeostasis. However, fundamental questions as to what the bona fide osteokines and their cellular sources are and how they are regulated remain unclear. In this study, we analyzed bone and extraskeletal tissues, osteoblast (OB) conditioned media, bone marrow supernatant (BMS), and serum, for basal osteokines and those responsive to aging and mechanical loading/unloading. We identified 375 candidate osteokines and their changes in response to aging and mechanical dynamics by integrating data from RNA-seq, scRNA-seq, and proteomic approaches. Furthermore, we analyzed their cellular sources in the bone and inter-organ communication facilitated by them (bone-brain, liver, and aorta). Notably, we discovered that senescent OBs secrete fatty-acid-binding protein 3 to propagate senescence toward vascular smooth muscle cells (VSMCs). Taken together, we identified previously unknown candidate osteokines and established a dynamic regulatory network among them, thus providing valuable resources to further investigate their systemic roles.

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Regenerative Rehabilitation represents a multifaceted approach that merges mechanobiology with therapeutic intervention to harness the body's intrinsic tissue repair and regeneration capacity. This review delves into the intricate interplay between mechanical loading and cellular responses in the context of musculoskeletal tissue healing. It emphasizes the importance of understanding the phases involved in translating mechanical forces into biochemical responses at the cellular level. The review paper also covers the mechanosensitivity of macrophages, fibroblasts, and mesenchymal stem cells, which play a crucial role during regenerative rehabilitation since these cells exhibit unique mechanoresponsiveness during different stages of the tissue healing process. Understanding how mechanical loading amplitude and frequency applied during regenerative rehabilitation influences macrophage polarization, fibroblast-to-myofibroblast transition (FMT), and mesenchymal stem cell differentiation is crucial for developing effective therapies for musculoskeletal tissues. In conclusion, this review underscores the significance of mechanome-guided strategies in regenerative rehabilitation. By exploring the mechanosensitivity of different cell types and their responses to mechanical loading, this field offers promising avenues for accelerating tissue healing and functional recovery, ultimately enhancing the quality of life for individuals with musculoskeletal injuries and degenerative diseases.