Figures
Fig. 1 Putative mechanisms of ECM stiffening and cellular contractile forces generated in response to increased microenvironment stiffness. (A) Matrix cross-linking by lysyl oxidase (LOX), tissue transglutaminase (TG2), and advanced glycation end products (AGEs) in concert with increased matrix deposition are major contributors of pathological matrix stiffening. Inside-out and outside-in extracellular matrix (ECM) rigidity sensing is transmitted across cell adhesions composed of integrins and focal adhesion complexes. (B) Actomyosin cell contractility forces are increased in response to elevated matrix stiffness, and traction forces are exerted against the ECM. Cellular force is also propagated across the cell cytoplasm to the nucleus. (C) Stiffness-mediated traction forces transmitted across integrins cause a conformational change in the transforming growth factor β (TGFβ) latency complex to release TGFβ ligand and activate positive feedback cycles of ECM synthesis and stiffening. Solid blue arrows represent directionality of force transmission.
CREDIT: A. KITTERMAN/SCIENCE TRANSLATIONAL MEDICINE
Fig. 2 Increased ECM stiffness activates the Rho-mediated cell contractility pathway. Mechanical force on integrins activates the Rho guanine nucleotide exchange factors (GEFs), GEF-H1 and LARG, to catalyze the exchange of guanosine diphosphate (GDP) for GTP. The major Rho effector Rho-associated kinase (ROCK) induces actomyosin cell contractility by phosphorylating myosin light chain phosphatase (MLCP) and myosin light chain (MLC). Downstream of Rho activation, myocardin-related transcription factor A (MRTF-A), yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ), nuclear factor κB (NF-κB), and mitogen-activated protein kinase (MAPK) pathways regulate gene expression, and Rho activity has pathological implications on cell survival, migration, proliferation, and ECM synthesis. Solid arrows indicate direction of cellular traction force generation (blue) and Rho-mediated contractility pathway events (black). Dashed black arrows represent cellular responses downstream of Rho-mediated cell contractility.
CREDIT: A. KITTERMAN/SCIENCE TRANSLATIONAL MEDICINE
Tables
- Table 1 Therapeutics in latest clinical trials with primary end points specific to ECM stiffness.
Target Drug name
(trade name/company)Category Highest
completed trialCurrent trials relevant
to ECM stiffnessReferences miR-29 MRG-201
(miRagen Therapeutics Inc.)MicroRNA Phase 1 None (26)
NCT02603224CTGF FG-3019 (Fibrogen) Monoclonal antibody Phase 2 Phase 2 (33, 34)
NCT01890265
NCT01262001TGFβ signaling Pirfenidone
(Esbriet/Genentech)Small molecule,
mechanism unknownApproved:
Idiopathic lung fibrosisPhase 1–3 (36)
NCT01872689
NCT02552849
NCT02408744
NCT03068234
NCT01872689TGFβ GC1008
(Fresolimumab/Genzyme)Monoclonal antibody Phase 2 Phase 1–2 (37)
NCT01401062
NCT02581787
NCT01665391VEGF, FGF, and
PDGF receptorsNintedanib
(Ofev/Boehringer Ingelheim)Small molecule, tyrosine
kinase inhibitorApproved:
Idiopathic lung fibrosisPhase 1–3 NCT01284322 LOXL2 GS-6624
(Simtuzumab/Gilead)Monoclonal antibody Phase 2
No efficacy in fibrosis
or cancerNone (56–58)
NCT01472198
NCT01759511
NCT 01769196LOX Tetrathiomolybdate Copper chelator Phase 3
(Wilson’s disease)Phase 2 (60)
NCT00805805
NCT00195091
NCT01837329αvβ6 BG00011/STX-100 (Biogen) Monoclonal antibody Phase 2 None (89)
NCT01371305FAK VS-6063/PF-04554878
(Defactinib/Verastem)Small molecule Phase 2 Phase 1–2 (117)
NCT02943317
NCT02758587
NCT02546531
NCT02465060FAK GSK-2256098
(GlaxoSmithKline)Small molecule Phase 1 Phase 1–2 (117)
NCT02551653
NCT02428270
NCT02523014NF-κB Bortezomib
(Velcade/Takeda)Small molecule Approved:
Multiple myelomaPhase 2 (138, 139)
NCT02370693 - Table 2 Select FDA-approved drugs with repurposing potential for mechano-based therapeutic interventions.
Drug Trade name Company Disease Target Reference Pirfenidone Esbriet Genentech Idiopathic lung fibrosis TGFβ signaling (36) Nintedanib Ofev Boehringer Ingelheim Idiopathic lung fibrosis VEGF, FGF,
and PDGF receptors(40) Statins Multiple Multiple Cardiovascular disease Rho, YAP/TAZ (98, 125) Verteporfin injection Visudyne Novartis Macular degeneration YAP (126) Bortezomib Velcade Takeda Multiple myeloma NF-κB (138, 139) Ixazomib Nilaro Takeda Multiple myeloma NF-κB (139) Carfilzomib Kyprolis Amgen Multiple myeloma NF-κB (138, 139) Vemurafenib Zelboraf Genentech Melanoma B-Raf (146) Dabrafenib Tafinlar Novartis Melanoma B-Raf (145, 146) Cobimetinib Cotellic Genentech Melanoma MEK (146) Trametinib Mekinist Novartis Melanoma MEK (145, 146)
