Bone Marrow Mesenchymal Stromal Cell Treatment in Patients with Osteoarthritis Results in Overall Improvement in Pain and Symptoms and Reduces Synovial Inflammation

Abstract

Patients with late‐stage Kellgren‐Lawrence knee osteoarthritis received a single intra‐articular injection of 1, 10, or 50 million bone marrow mesenchymal stromal cells (BM‐MSCs) in a phase I/IIa trial to assess safety and efficacy using a broad toolset of analytical methods. Besides safety, outcomes included patient‐reported outcome measures (PROMs): Knee Injury and Osteoarthritis Outcome Score (KOOS) and Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC); contrast‐enhanced magnetic resonance imaging (MRI) for cartilage morphology (Whole Organ MRI Scores [WORMS]), collagen content (T2 scores), and synovitis; and inflammation and cartilage turnover biomarkers, all over 12 months. BM‐MSCs were characterized by a panel of anti‐inflammatory markers to predict clinical efficacy. There were no serious adverse events, although four patients had minor, transient adverse events. There were significant overall improvements in KOOS pain, symptoms, quality of life, and WOMAC stiffness relative to baseline; the 50 million dose achieved clinically relevant improvements across most PROMs. WORMS and T2 scores did not change relative to baseline. However, cartilage catabolic biomarkers and MRI synovitis were significantly lower at higher doses. Pro‐inflammatory monocytes/macrophages and interleukin 12 levels decreased in the synovial fluid after MSC injection. The panel of BM‐MSC anti‐inflammatory markers was strongly predictive of PROMs over 12 months. Autologous BM‐MSCs are safe and result in significant improvements in PROMs at 12 months. Our analytical tools provide important insights into BM‐MSC dosing and BM‐MSC reduction of synovial inflammation and cartilage degradation and provide a highly predictive donor selection criterion that will be critical in translating MSC therapy for osteoarthritis. Stem Cells Translational Medicine 2019;8:746&757

Macrophage: A Potential Target on Cartilage Regeneration

“…NF-kB represents a family of inducible dimeric transcription factors that stimulates osteoarthritis and it is a pivotal factor that induces suppression of the chondrogenic potential of human osteoarthritic synovial MSCs (52). Chahal et al (75) demonstrated a reduced level of monocytes/macrophages proinflammatory IL-12 cytokine in synovial fluid levels and likely improved clinical efficacy in patient-reported outcomes after 3 months of high doses of MSCs injection in the knee (75).…”

Iron nanoparticle-labeled murine mesenchymal stromal cells in an osteoarthritic model persists and suggests anti-inflammatory mechanism of action

“…Early clinical data shows improvements in cartilage volume and quality [2][3][4][5][6][7] and secretion of immunomodulatory factors. Our pioneering Canadian trial (NCT02351011, clinicaltrials.gov) using autologous bone-marrow-derived MSCs showed significant improvement in symptoms and quality of life relative to baseline in osteoarthritic patients; for the first time, we showed clinically that MSCs reduced synovial joint levels of pro-inflammatory macrophages, a potent inflammatory mediator, suggestive of a possible mechanism of action [8]. Macrophages are the most prevalent immune cell in OA joints [9], are elevated in OA compared to healthy joints [10], and contribute to synovial inflammation and fibrosis, characteristic of OA.…”

Iron nanoparticle-labeled murine mesenchymal stromal cells in an osteoarthritic model persists and demonstrates anti-inflammatory mechanism of action

“…Early clinical data shows improvements in cartilage volume and quality [1][2][3][4][5][6] and secretion of immunomodulatory factors. Our pioneering Canadian trial (NCT02351011, clinicaltrials.gov) using autologous bone-marrow-derived MSCs showed significant improvement in symptoms and quality of life relative to baseline in osteoarthritic patients; for the first time, we showed clinically that MSCs reduced synovial joint levels of pro-inflammatory macrophages, a potent inflammatory mediator, suggestive of a possible mechanism of action [7]. Macrophages are the most prevalent immune cell in OA joints [8], are elevated in OA compared to healthy joints [9], and contribute to synovial inflammation and fibrosis, characteristic of OA.…”

“…After labeling, cells underwent sequential PBS washing before and after dissociation. All cells (Fe-MSCs and unlabeled MSCs) were stained with the lipophilic fluorescent dye DiR (also called DiIC18 (7), full chemical name:…”