Anti-Inflammatory Therapeutic Approaches to Prevent or Delay Post-Traumatic Osteoarthritis (PTOA) of the Knee Joint with a Focus on Sustained Delivery Approaches
Abstract
:1. Introduction
2. Methodology
3. A Brief Description of the Cells and Tissues That Participate in the Pathogenesis and Progression of PTOA within the Knee Joint
4. Anti-Inflammatory Therapeutic Interventions to Prevent or Treat PTOA of the Knee Joint
4.1. Dexamethasone
4.2. Triamcinolone Acetonide (TCA)
4.3. Hyaluronic Acid (HA)
4.4. Inhibitors of TNF-α and Interleukin-1 Receptor Antagonist (IL-1ra)
4.5. Anti-IL-6 Receptor Antibody
4.6. Anti-Inflammatory Cytokines IL-4, IL-10 and IL-13
4.7. Complement Inhibitors
4.8. Tranexamic Acid (TXA)
5. Possible Sustained Delivery Approaches to Prevent or Delay Knee PTOA
6. Discussion
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ACAN | Aggrecan |
ACLT | Anterior cruciate ligament transection |
ACS | autologous conditioned serum |
ADAMTS | A disintegrin and metalloproteinase with thrombospondin motifs |
bFGF | Basic fibroblast growth factor |
C1INH | C1 inhibitor |
COLI | Collagen I |
COLII | Collagen II |
COMP | Cartilage oligomeric matrix protein |
CTX-I | C-terminal crosslinked telopeptide type I collagen |
CTX-II | C-terminal crosslinked telopeptide type II collagen |
CXCL | Chemokine ligand |
ECM | Extracellular matrix |
ELP | Elastine-like polypeptide |
GAG | Glycosaminoglycan |
GlcNAc | N-acetylglucosamine |
gp130 | Glycoprotein 130 |
HA | Hyaluronic acid (HA) |
IFN-ɣ | Interferon-gamma |
IGF-1 | Insulin-like growth factor 1 |
IL | Interleukin |
IL-1ra | IL-1 receptor antagonist |
IL-6R | IL-6 receptor |
i.a. | Intra-articular |
i.p. | Intraperitoneal |
i.v. | Intravenous |
iNOS | Inducible NO synthase |
IGF-1 | Insulin-like growth factor 1 |
kDa | Kilodalton |
KOOS | Knee Injury and Osteoarthritis Outcome Score |
LPS | Lipopolysaccharide |
MAC | Membrane attack complex |
MCLT | medial collateral ligament transection |
MSC | Mesenchymal stem/stromal cells |
MCP-1 | Monocyte chemoattractant protein-1, also known as CCL2 |
MIP-1 | Macrophage inflammatory protein-1 |
MMPs | Matrix metalloproteinases |
MW | molecular weight |
MRI | Magnetic resonance imaging |
NO | Nitric oxide |
NOS2 | Nitric Oxide Synthase 2 |
NSAIDS | nonsteroidal anti-inflammatory drugs |
OA | Osteoarthritis |
PCM | Pericellular matrix |
PDGF | Platelet-derived growth factor |
PEA | Polyester amide |
PGPS | peptidoglycan-polysaccharide streptococcal |
PEG | Polyethylene glycol |
PGE2 | Prostaglandin E₂ |
PLGA | Poly (lactic-co-glycolic acid) |
PTOA | Post-traumatic osteoarthritis |
RA | Rheumatoid arthritis |
s.c. | subcutaneous |
sIL-6R | Soluble IL-6 receptor |
sTNFRII | Soluble TNF receptor II |
TCA | Triamcinolone acetonide |
TCC | Terminal complement complex |
TACE | Tumor necrosis factor-α converting enzyme |
TGF-β | transforming growth factor-beta |
TIMP | Tissue inhibitor of metalloproteinases |
TNF-α | Tumor necrosis factor-alpha |
Th | T helper |
TSG-6 | TNF-stimulated gene 6 protein |
TXA | Tranexamic Acid |
WOMAC | The Western Ontario and McMaster Universities Osteoarthritis |
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Clinical Anti-Inflammatory Approaches to Prevent or Delay Knee PTOA | |||||
---|---|---|---|---|---|
Intervention | Trial Name | Patient Criteria | Study Design | Outcome | Benefit Observed |
Triamcinolone acetonide from PLGA microspheres (FX006, Zilretta®) | Success of Long-acting Anti-inflammatories After Anterior Cruciate Ligament and Meniscal Injury (SLAM) (NCT04331002) | Elevated synovial fluid IL-6 remaining 4 weeks after ACL reconstruction with meniscal involvement (Age 18–40 years) | Single i.a. injection 8 weeks after ACL reconstruction in a Phase 2, randomized, quadruple blinded, parallel assignment, placebo-controlled study | Bone Shape, IKDC, KOOS Global ICOAP at baseline, 4 months, 1 year and 2 years after intervention; CTX-II levels only at baseline and 4 months | Recruiting |
Triamcinolone acetonide alone (Kenalog®-40) vs. Triamcinolone acetonide from PLGA microspheres (FX006, Zilretta®) | Proof of Concept Study Comparing FX006 to Kenalog®-40 in Patients With Post-Traumatic Osteoarthritis of the Knee (NCT02468583) | Kellgren-Lawrence (KL) Grade 2 or 3 PTOA (Age 20–50 years) | Single i.a. injection in a Phase 2, randomized, quadruple blinded, parallel assignment study | Pain intensity score using NRS, WOMAC—(A1, B, C and Total), KOOS, PGIC, CGIC, % of responders according to OMERACT-OARSI criteria, time to onset of pain relief and average weekly and total consumption of rescue medication over 12 weeks after intervention | Data not yet available |
Recombinant human IL-1ra (Anakinra®) | Study to Prevent Cartilage Damage Following Acute Knee Injury (NCT00332254) [25] | Onset of a sports-related ACL tear requiring surgery (Age 18–30 years) | Single i.a. injection within 4 weeks (a mean 15 ± 7 days) of knee injury in a Phase 1/2, randomized, quadruple blinded, parallel assignment, placebo-controlled study involving 11 patients | KOOS at baseline before treatment, 4 and 14 days after intervention; SF IL-1α, IL-1β and IL-1ra levels and serum HA at baseline and a mean of 35 days after treatment | Improvement in KOOS, decrease in SF IL-1α within 2 weeks of treatment |
Recombinant human IL-1ra (Anakinra®) | Study to Early PTOA Following Acute Knee Injury (NCT02930122) | ACL tear and painful effusions (Age 14–40 years) | Single i.a. injection within 4 weeks of injury in a Phase 2 prospective, single-center, randomized, triple-blinded, placebo-controlled study | CTX-II levels from injury to time of surgery, KOOS scores and quantitative T1rho MRI 1 year after injury | Data not yet available |
Therapeutic Agent | Drug Delivery | Pre-Clinical and Clinical Studies | Effect | Company/ References |
---|---|---|---|---|
Dexamethasone | Lipid-based microspheres (TLC599, BioSeizer®) | Phase 2 (OA-associated knee pain) | Reduced pain | TLC, [67] |
Dexamethasone | Avidin | Bovine cartilage explant (IL-1α) model PTOA (ACLT) rabbit model | Rescued IL-1α induced cell death and decreased cartilage degeneration Decreased inflammation and cartilage degeneration | [53,65,66] |
Triamcinolone Acetonide | PLGA microspheres (FX006, Zilretta®) | FDA approved (OA-associated knee pain); Phase 2 (PTOA, ACL injury) Acute synovitis (PGPS) rat model | Reduced pain Results not yet published Decreased inflammation and cartilage degeneration | Flexion Therapeutics [70] NCT04331002 NCT02468583 [79] |
Triamcinolone Acetonide | PEA microspheres | OA (type II collagenase) rat model; Acute synovitis (bacterial PGPS) rat model | Decreased inflammation but was not capable of decreasing cartilage degeneration | [77,78] |
IL-1rawith or withoutsTNFRII | Elastin-like polypeptide (Anakinra® vs. Etanercept®) | PTOA (MCLT) mouse model | IL-1ra decreased inflammation and cartilage degeneration sTNFRII had adverse effects on cartilage and bone and caused synovial inflammation | [109] |
IL-1ra | PLGA microspheres (Anakinra®) | PTOA (ACL tear) rat model | Decreased inflammation and cartilage degeneration | [124] |
IL-1ra | Gene therapy Adenovirus vector under with NF-kB-responsive promoter (FX201) | Phase 1 (Knee OA) | Results not yet published | NCT04119687 |
IL-1ra | HA-chitosan microspheres | Rat chondrocyte (IL-1β) model | Decreased inflammation and chondrocyte apoptosis | [125] |
IL-1ra and IL-10 | Gene therapy retrovirus vector | PTOA (MCL+MM) rabbit model | Decreased cartilage degeneration | [217] |
IL-4 and IL-10 | Fusion protein | Human OA knee cartilage and synovium; PTOA (groove) canine model | Decreased inflammation, improved PG turnover and reduced pain | [174] |
IL-4 and IL-10 | Fusion protein | Human healthy cartilage (50% v/v blood-injury model); PTOA (joint bleeding) hemophilic mouse model | Decreased cartilage degeneration | [212,213] |
IL-10 | Gene therapy lentivirus vector with CXCL10-responsive promoter | RA synovial cell and THP-1 monocyte cell line (LPS) models; Human OA synovial membrane/Matrigel 3D culture (TNF-α or LPS) model | Decreased inflammation | [218,219] |
IL-4, IL-13 or IL-10 | Gelatin microspheres | ATDC-5 mouse chondrocyte (IL-1β or LPS) model | IL-4 and IL-13 decreased NO production | [199] |
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Khella, C.M.; Horvath, J.M.; Asgarian, R.; Rolauffs, B.; Hart, M.L. Anti-Inflammatory Therapeutic Approaches to Prevent or Delay Post-Traumatic Osteoarthritis (PTOA) of the Knee Joint with a Focus on Sustained Delivery Approaches. Int. J. Mol. Sci. 2021, 22, 8005. https://doi.org/10.3390/ijms22158005
Khella CM, Horvath JM, Asgarian R, Rolauffs B, Hart ML. Anti-Inflammatory Therapeutic Approaches to Prevent or Delay Post-Traumatic Osteoarthritis (PTOA) of the Knee Joint with a Focus on Sustained Delivery Approaches. International Journal of Molecular Sciences. 2021; 22(15):8005. https://doi.org/10.3390/ijms22158005
Chicago/Turabian StyleKhella, Christine M., Judith M. Horvath, Rojiar Asgarian, Bernd Rolauffs, and Melanie L. Hart. 2021. "Anti-Inflammatory Therapeutic Approaches to Prevent or Delay Post-Traumatic Osteoarthritis (PTOA) of the Knee Joint with a Focus on Sustained Delivery Approaches" International Journal of Molecular Sciences 22, no. 15: 8005. https://doi.org/10.3390/ijms22158005