Musculoskeletal mechanobiology: A new era for MechanoMedicine

Guo, Xiaolei; Hung, Clark T.; Sandell, Linda J.; Silva, Matthew J.

doi:10.1002/jor.23789

Cited by 7 publications

(4 citation statements)

References 27 publications

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“…In summary, increasing evidence supports applying controlled mechanical loading as a therapeutic treatment in musculoskeletal repair. (58) Understanding the effect of mechanical loading on the spatiotemporal distribution and activities of angiogenic and osteogenic progenitors during bone repair is essential for developing and optimizing treatments for injuries in load-bearing bone, particularly for complications relating to diminished vascularization, such as delayed unions and nonunions. Here we show that within a healing cortical defect, blood vessels, progenitor cell populations, and the growing bone matrix are intimately organized in time and space, suggesting tightly orchestrated remodeling events.…”

Section: Discussionmentioning

confidence: 99%

Mechanical Loading Promotes the Expansion of Primitive Osteoprogenitors and Organizes Matrix and Vascular Morphology in Long Bone Defects

Liu

Cabahug‐Zuckerman

Stubbs

et al. 2019

Journal of Bone and Mineral Research

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Elucidating the effects of mechanical stimulation on bone repair is crucial for optimization of the healing process. Specifically, the regulatory role that mechanical loading exerts on the osteogenic stem cell pool and vascular morphology during healing is incompletely understood. Because dynamic loading has been shown to enhance osteogenesis and repair, we hypothesized that loading induces the expansion of the osteoprogenitor cell population within a healing bone defect, leading to an increased presence of osteogenic cells. We further hypothesized that loading during the repair process regulates vascular and collagen matrix morphology and spatial interactions between vessels and osteogenic cells. To address these hypotheses, we used a mechanobiological bone repair model, which produces a consistent and reproducible intramembranous repair response confined in time and space. Bilateral tibial defects were created in adult C57BL/6 mice, which were subjected to axial compressive dynamic loading either during the early cellular invasion phase on postsurgical days (PSDs) 2 to 5 or during the matrix deposition phase on PSD 5 to 8. Confocal and two‐photon microscopy was used to generate high‐resolution three‐dimensional (3D) renderings of longitudinal thick sections of the defect on PSD 10. Endomucin (EMCN)‐positive vessels, Paired related homeobox 1 (Prrx1+) stem cell antigen‐1 positive (Sca‐1+) primitive osteoprogenitors (OPCs), and osterix positive (Osx+) preosteoblasts were visualized and quantified using deep tissue immunohistochemistry. New bone matrix was visualized with second harmonic generation autofluorescence of collagen fibers. We found that mechanical loading during the matrix deposition phase (PSD 5 to 8) increased vessel volume and number, and aligned vessels and collagen fibers to the load‐bearing direction of bone. Furthermore, loading led to a significant increase in the proliferation and number of Prrx1+ Sca‐1+ primitive OPCs, but not Osx+ preosteoblasts within the defect. Together, these data illustrate the adaptation of both collagen matrix and vascular morphology to better withstand mechanical load during bone repair, and that the mechanoresponsive cell population consists of the primitive osteogenic progenitors. © 2019 American Society for Bone and Mineral Research.

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Section: Discussionmentioning

confidence: 99%

Mechanical Loading Promotes the Expansion of Primitive Osteoprogenitors and Organizes Matrix and Vascular Morphology in Long Bone Defects

Liu

Cabahug‐Zuckerman

Stubbs

et al. 2019

Journal of Bone and Mineral Research

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“…Unlocking the mechanisms leading from mechanical stimuli to cellular sensing and response has become necessary to understand and tackle diseases in essentially all medical disciplines [1]. Musculoskeletal disorders are often associated with abnormal mechanical stress applied to load-bearing tissues [2,3]. In the intervertebral disc (IVD), compressive forces from the body weight and spinal motions generate hydrostatic and osmotic pressures in the central gelatinous nucleus pulposus, which in turn increase tensile stresses in the ring-shaped annulus fibrosus (AF) [4].…”

Section: Introductionmentioning

confidence: 99%

TRPV4 Inhibition and CRISPR-Cas9 Knockout Reduce Inflammation Induced by Hyperphysiological Stretching in Human Annulus Fibrosus Cells

Cambria

Arlt

Wandel

et al. 2020

Cells

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Mechanical loading and inflammation interact to cause degenerative disc disease and low back pain (LBP). However, the underlying mechanosensing and mechanotransductive pathways are poorly understood. This results in untargeted pharmacological treatments that do not take the mechanical aspect of LBP into account. We investigated the role of the mechanosensitive ion channel TRPV4 in stretch-induced inflammation in human annulus fibrosus (AF) cells. The cells were cyclically stretched to 20% hyperphysiological strain. TRPV4 was either inhibited with the selective TRPV4 antagonist GSK2193874 or knocked out (KO) via CRISPR-Cas9 gene editing. The gene expression, inflammatory mediator release and MAPK pathway activation were analyzed. Hyperphysiological cyclic stretching significantly increased the IL6, IL8, and COX2 mRNA, PGE2 release, and activated p38 MAPK. The TRPV4 pharmacological inhibition significantly attenuated these effects. TRPV4 KO further prevented the stretch-induced upregulation of IL8 mRNA and reduced IL6 and IL8 release, thus supporting the inhibition data. We provide novel evidence that TRPV4 transduces hyperphysiological mechanical signals into inflammatory responses in human AF cells, possibly via p38. Additionally, we show for the first time the successful gene editing of human AF cells via CRISPR-Cas9. The pharmacological inhibition or CRISPR-based targeting of TRPV4 may constitute a potential therapeutic strategy to tackle discogenic LBP in patients with AF injury.

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“…The study of mechanobiology and electrobiology in orthopedics—in both basic and translational science—can also inform therapies and pharmaceutical interventions in clinical medicine [ 107 ]. For instance, the discipline of rehabilitation medicine utilizes a variety of physical stimuli—including electrical, thermal, and mechanical stimulation—effectively in the clinic [ 108 ].…”

Section: Discussionmentioning

confidence: 99%

Biophysical Modulation of Mesenchymal Stem Cell Differentiation in the Context of Skeletal Repair

Hung

Racine-Avila

Pellicore

et al. 2022

IJMS

Self Cite

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A prominent feature of the skeleton is its ability to remodel in response to biophysical stimuli and to repair under varied biophysical conditions. This allows the skeleton considerable adaptation to meet its physiological roles of stability and movement. Skeletal cells and their mesenchymal precursors exist in a native environment rich with biophysical signals, and they sense and respond to those signals to meet organismal demands of the skeleton. While mechanical strain is the most recognized of the skeletal biophysical stimuli, signaling phenomena also include fluid flow, hydrostatic pressure, shear stress, and ion-movement-related electrokinetic phenomena including, prominently, streaming potentials. Because of the complex interactions of these electromechanical signals, it is difficult to isolate the significance of each. The application of external electrical and electromagnetic fields allows an exploration of the effects of these stimuli on cell differentiation and extra-cellular matrix formation in the absence of mechanical strain. This review takes a distinctly translational approach to mechanistic and preclinical studies of differentiation and skeletal lineage commitment of mesenchymal cells under biophysical stimulation. In vitro studies facilitate the examination of isolated cellular responses while in vivo studies permit the observation of cell differentiation and extracellular matrix synthesis.

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Musculoskeletal mechanobiology: A new era for MechanoMedicine

Cited by 7 publications

References 27 publications

Mechanical Loading Promotes the Expansion of Primitive Osteoprogenitors and Organizes Matrix and Vascular Morphology in Long Bone Defects

Mechanical Loading Promotes the Expansion of Primitive Osteoprogenitors and Organizes Matrix and Vascular Morphology in Long Bone Defects

TRPV4 Inhibition and CRISPR-Cas9 Knockout Reduce Inflammation Induced by Hyperphysiological Stretching in Human Annulus Fibrosus Cells

Biophysical Modulation of Mesenchymal Stem Cell Differentiation in the Context of Skeletal Repair

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