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Review Open Access

Mechanotransduction and its impact on regenerative medicine in orthopedic rehabilitation (Review)

  • Authors:
    • Baohui Wang
    • Xueqin Zeng
    • Huajian Liu
    • Liang Li
    • Tao Lei
    • Yafeng Li
    • Qing Fang
    • Yi Cao
    • Bo Dong
  • View Affiliations / Copyright

    Affiliations: Pain Ward, Department of Rehabilitation, Honghui Hospital, Xi'an Jiaotong University, Xi'an, Shaanxi 710000, P.R. China
    Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 127
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    Published online on: March 13, 2026
       https://doi.org/10.3892/ijmm.2026.5798
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Abstract

Mechanotransduction, the process by which cells convert mechanical stimuli into biochemical signals, serves as a fundamental biological mechanism driving tissue adaptation and repair in orthopedic rehabilitation. The present review explores how mechanical forces regulate cellular behavior in bone, cartilage, tendon and ligament healing, emphasizing their critical role in optimizing regenerative outcomes. Specialized mechanosensors, including integrins, ion channels and primary cilia, detect physical cues such as compression, tension and shear stress, activating downstream pathways that direct stem cell differentiation, matrix synthesis and tissue remodeling. The extracellular matrix functions not only as a structural scaffold but also as a dynamic mediator of mechanical signaling, influencing cellular responses to therapeutic loading. Clinically, mechanotherapy strategies, including controlled weight‑bearing, eccentric exercises and devices providing dynamic compression, are designed to exploit these principles, promoting anabolic activity while preventing catabolic damage. Advances in biomechanically optimized scaffolds, bioreactor systems and technologies (such as low‑intensity pulsed ultrasound) further demonstrate how targeted mechanical conditioning enhances tissue‑engineered constructs and accelerates functional recovery. However, challenges remain in defining optimal loading parameters across diverse tissues and individual patients. Future directions should prioritize personalized rehabilitation protocols informed by real‑time biomechanical monitoring and genetic profiling, alongside biomaterials that can adapt to in vivo mechanical cues. The integration of mechanobiology with regenerative medicine is paving the way for a new era in orthopedic rehabilitation. This evolution promises more precise, effective and biologically driven interventions that harness the innate mechanoresponsive capacity of the body to restore function.
View Figures

Figure 1

Mechanotransduction is fundamental to
distraction histogenesis. Mechanotransduction begins when
mechanical forces are applied to the ECM and cellular membranes,
which in turn stimulate mechanosensitive ion channels, including
Piezo1. The activation of these channels initiates downstream
signaling cascades such as the Wnt/β-catenin, MAPK, PI3K/AKT and
mTOR pathways that regulate critical cellular processes, including
proliferation and differentiation. Concurrently, this
mechanosensitive signaling stimulates the production of growth
factors, namely TGF-β1, PDGF-BB and VEGF. These factors are then
released into the circulation and transported to the injury site,
where they promote bone lengthening and regeneration, in addition
to supporting the repair and neogenesis of vascular and cutaneous
tissues. ECM, extracellular matrix; LRP, lipoprotein
receptor-related protein; GSK-3β, glycogen synthase kinase 3β;
CKIα, casein kinase 1α; APC, adenomatous polyposis coli; TCF/LEF,
T-cell factor and lymphoid enhancer-binding factor; RAS, rat
sarcoma; Raf, rapidly accelerated fibrosarcoma; ERK, extracellular
signal-regulated kinase; shc, SHC-adaptor protein; GRB2, growth
factor receptor-bound protein; RTK, receptor tyrosine kinase; TSC1,
tuberous sclerosis complex 1; Rheb, Ras homolog enriched in brain;
PDGF-BB, platelet-derived growth factor-BB.

Figure 2

Osteogenic differentiation pathway
driven by mechanotransduction. Mechanical signals promote the
commitment of MSCs to the osteoblast lineage by activating key
transcription factors (such as β-catenin, RUNX2 and MSX2) while
inhibiting drivers of alternative fates (such as PPARγ, MyoD and
SOX9). The progression from osteoprogenitor to pre-osteoblast to
functional osteoblast is marked by the sequential expression of
characteristic genes (such as ALP, COL1A1, BSP and OCN). The final
fate of the osteoblast is either apoptosis or incorporation into
the bone structure as a lining cell. This mechanically-induced
osteogenesis is crucial for bone formation and regeneration in
orthopedic rehabilitation. MSC, mesenchymal stem cell; PPAR-γ,
peroxisome proliferator-activated receptor γ; MyoD, myoblast
determination protein; SOX9, SRY-box transcription factor 9; RUNX2,
Runt-related transcription factor 2; MSX2, Msh homeobox 2; FOXP1,
forkhead box P1, MAF, macrophage-activating factor; ATF4,
activating transcription factor 4; FAR1, fatty acyl-CoA reductase
1; ALP, alkaline phosphatase; COL1A1, collagen type I α1 chain;
BSP, bone sialoprotein; OCN, osteocalcin; OSX, osterix.

Figure 3

Mechanosignaling in bone cells. This
schematic depicts how bone cells perceive mechanical forces and
translate them into biological activity, both within themselves and
across cell-to-cell junctions. The pathway initiates with
mechanical signals being detected by sensors on the cell surface
(such as integrins and ion channels) and the cytoskeleton. This
triggers mechanotransduction via signaling pathways (such as Hippo
and Wnt), leading to the generation of signaling molecules.
Intracellularly, key TFs (such as YAP/TAZ, β-catenin and RUNX2) are
activated and translocate to the nucleus to mediate transcriptional
regulation of target genes (such as BGLAP and SPP1) essential for
bone formation. Furthermore, these signals are communicated to
neighboring cells via receptor-mediated cell-cell interactions
(such as through gap junctions or paracrine signaling),
coordinating a synchronized anabolic response across the bone
tissue. ECM; extracellular matrix; TF, transcription factor; YAP,
Yes-associated protein; TAZ, transcriptional coactivator with
PDZ-binding motif; RUNX2, Runt-related transcription factor 2;
BGLAP, bone γ-carboxyglutamate protein; SPP1, secreted
phosphoprotein 1.

Figure 4

Nuclear mechanotransduction drives
osteogenic transcription. Mechanical forces are transduced from the
cytoskeleton (F-actin) to the nucleus via the LINC complex,
inducing nuclear deformation. This strain enhances the permeability
of nuclear pore complexes, facilitating the accelerated nuclear
import of key transcription factors and coactivators. The
mechanosensitive regulators YAP/TAZ and β-catenin accumulate within
the nucleus, where they orchestrate the upregulation of osteogenic
gene programs. Concurrently, phosphorylated RUNX2 binds to target
sites, inducing chromatin remodeling to an open conformation, which
further potentiates the transcriptional activation of genes
essential for bone formation. LINC; linker of nucleoskeleton and
cytoskeleton; SUN, Sad1-UNC-84 homology; KASH, Klarsicht, ANC-1,
syne homology; ERK, extracellular signal-regulated kinase; YAP,
Yes-associated protein; TAZ, transcriptional coactivator with
PDZ-binding motif; RUNX2, runt-related transcription factor 2; TCF,
T-cell factor; LEF, lymphoid enhancer factor; LCF, transcription
cofactor; TEAD, transcriptional enhanced associate domain.
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Copy and paste a formatted citation
Spandidos Publications style
Wang B, Zeng X, Liu H, Li L, Lei T, Li Y, Fang Q, Cao Y and Dong B: Mechanotransduction and its impact on regenerative medicine in orthopedic rehabilitation (Review). Int J Mol Med 57: 127, 2026.
APA
Wang, B., Zeng, X., Liu, H., Li, L., Lei, T., Li, Y. ... Dong, B. (2026). Mechanotransduction and its impact on regenerative medicine in orthopedic rehabilitation (Review). International Journal of Molecular Medicine, 57, 127. https://doi.org/10.3892/ijmm.2026.5798
MLA
Wang, B., Zeng, X., Liu, H., Li, L., Lei, T., Li, Y., Fang, Q., Cao, Y., Dong, B."Mechanotransduction and its impact on regenerative medicine in orthopedic rehabilitation (Review)". International Journal of Molecular Medicine 57.5 (2026): 127.
Chicago
Wang, B., Zeng, X., Liu, H., Li, L., Lei, T., Li, Y., Fang, Q., Cao, Y., Dong, B."Mechanotransduction and its impact on regenerative medicine in orthopedic rehabilitation (Review)". International Journal of Molecular Medicine 57, no. 5 (2026): 127. https://doi.org/10.3892/ijmm.2026.5798
Copy and paste a formatted citation
x
Spandidos Publications style
Wang B, Zeng X, Liu H, Li L, Lei T, Li Y, Fang Q, Cao Y and Dong B: Mechanotransduction and its impact on regenerative medicine in orthopedic rehabilitation (Review). Int J Mol Med 57: 127, 2026.
APA
Wang, B., Zeng, X., Liu, H., Li, L., Lei, T., Li, Y. ... Dong, B. (2026). Mechanotransduction and its impact on regenerative medicine in orthopedic rehabilitation (Review). International Journal of Molecular Medicine, 57, 127. https://doi.org/10.3892/ijmm.2026.5798
MLA
Wang, B., Zeng, X., Liu, H., Li, L., Lei, T., Li, Y., Fang, Q., Cao, Y., Dong, B."Mechanotransduction and its impact on regenerative medicine in orthopedic rehabilitation (Review)". International Journal of Molecular Medicine 57.5 (2026): 127.
Chicago
Wang, B., Zeng, X., Liu, H., Li, L., Lei, T., Li, Y., Fang, Q., Cao, Y., Dong, B."Mechanotransduction and its impact on regenerative medicine in orthopedic rehabilitation (Review)". International Journal of Molecular Medicine 57, no. 5 (2026): 127. https://doi.org/10.3892/ijmm.2026.5798
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