Table 1.
Selected pre-clinical and clinical studies on bone effects of senolytics.
| Agent | Setting | Intervention | Main Effects | Reference | |
|---|---|---|---|---|---|
| Pre-clincial | |||||
| Dasatinib | In vitro | Human BMSCs | 2–5 nM, 7 or 21 d | Tyrosine kinases (PDGFR-ß, c-SRC, c-Kit) ↓, canonical Wnt signaling pathway ↑ | Garcia-Gomez et al. [73] |
| Dasatinib | In vitro | Human PBMCs | 2–2.5 nM, 7 or 14 d | Oc differentiation↓ (c-Fos ↓, NFATc1 ↓), Oc function ↓ (cathepsin K ↓, αVß3 integrin ↓, CCR1 ↓) | Garcia-Gomez et al. [73] |
| Dasatinib | In vivo | Young mice | 2.5 or 10 mg/kg p.o., 3 or 7 we | Serum levels of ALP ↑, Oc ↑, and TRAP5b ≈, osteoblast-like cells ↑, trabecular structure ↑ | Garcia-Gomez et al. [73] |
| Quercetin | In vitro | Rat BMSCs | 33.8 µg/mL, 24 h | senescent BMSCs ↓, BMSCs proliferation ↑, osteogenic potential ↑ (osterix ↑, RUNX2 ↑) | Zhang et al. [74] |
| Quercetin | In vivo | Rat model | Quercetin release system on titanium implants | Osseointegration ↑ | Wang et al. [75] |
| Dasatinib + quercetin | In vivo | Aged C57BL/6 J mice | Dasatinib 5 mg/kg + quercetin 50 mg/kg p.o. per month, 4 months | Senescent osteocytes ↓, osteoclasts ↓, osteoblasts ≈, trabecular microarchitecture at spine and femur ↑, cortical microarchitecture at femur ↑ | Farr et al. [42] |
| Dasatinib + quercetin | In vivo | C57BL/6 J mice | Dasatinib 5 mg/kg + quercetin 50 mg/kg p.o. 0 and 14 d after FRT of femur; bones harvested 42 d post FRT | P1NP ↑, CTX ≈, osteoblasts ↑, OCN ≈, RUNX2 ≈, BV/TV ↑, connectivity density ↑, BFR/BS ↑ | Chandra et al. [51] |
| Dasatinib + quercetin | In vitro | BMSCs of young and old mice | Dasatinib 0.2 µM + quercetin 20 µM, 24 h | SABG + BMSCs ↓, BMSC proliferation ↑, OCN ↑, bone sialoprotein ↑ | Zhou et al. [76] |
| Dasatinib + quercetin | In vivo | Immunodeficient mice | Old BMSCs: dasatinib 0.2 µM + quercetin 20 µM, 24 h => implanted into calvarial defect | TRAP ↑, ALP ↑, osteogenic capacity of aged BMSCs ↑ | Zhou et al. [76] |
| Dasatinib + quercetin | In vitro | Mouse MSCs | Induction of senescence => Dasatinib 200 nM + quercetin 50 µM, 24 h | Senescence in MSCs ↓ | Saul et al. [77] |
| Dasatinib + quercetin | In vivo | Mice | Dasatinib 5 mg/kg + quercetin 50 mg/kg p.o., 5 w | MSCs ↑, senescent MSCs ↓ | Saul et al. [77] |
| Dasatinib + quercetin | In vivo | Mice | Dasatinib 5 mg/kg + quercetin 50 mg/kg once => induction of fracture p.o. => Dasatinib 5 mg/kg + quercetin 50 mg/kg p.o., 5 w | SASP in callus ↓, fracture healing time ↓, maximal torque after 2 w ↑ | Saul et al. [77] |
| Navitoclax | In vitro | Radiation induced senesent HUVECs | 100 nM to 1 uM up to 3 d | Apoptosis ↑; no effect on non-senesent cells | Zhu et al. [78] |
| Navitoclax | In vivo | Young sublethally irradiated and aged p16-3MR transgenic mice and C57/BL6 mice | 50 mg/kg/d p.o., 2 cycles of 7 d, 2 w break in between | Number of HSCs and HPCs ≈, rejuvenates aged HSCs (for instance persistent DNA damage ↓); SASP ↓ | Chang et al. [36] |
| Navitoclax | In vitro | Osteoprogenitor cells of old Osx1-Cre;TdRFP mice | 5 µM, 5 d | Apoptosis of BMSCs ↑ SASP ↓, RANK L ↓ |
Kim et al. [79] |
| Navitoclax | In vitro | Human BMSCs | 10 µM, 3 d | Senescent human BMSCs ↓ | Grezella et al. [80] |
| Fisetin | In vitro | BMSCs of 3–5 week-old C57/BL6 mice, osteoclast precursors Raw264.7 cells | 1–10 µM, 7/4 d | TRAP ↓, CTR ↓, MMP9 ↓, cathepsin K ↓, NF-kB pathway ↓, p38 MAPK/JNK ↓, c-FOS/NFATc1 ↓, MKP-1 ↑ => osteoclastogenesis ↓ | Léotoing et al. [81] |
| Fisetin | In vivo | Young C57/BL6 mice | 5–50 mg/kg p.o., 1 w => OVX => 5–25 mg/kg p.o., 4 w | BMD ↑, BV/TV ↑, TbN ↑, TbTh ↑ | Léotoing et al. [81] |
| Fisetin | In vivo | Young C57/BL6 mice | LPS s.c. 1/w for 3 w and fisetin 5–50 mg/kg p.o. | BMD ↑, BV/TV ↑, TbN ↑ | Leotoing et al. [81] |
| Fisetin | In vitro | MC3T3-E1 mouse preosteoblasts | 0–800 nM, 14 d | ALP ↑, RUNX2 ↑, Col1α1 ↑, OSX ↑, OCN ↑, BMP4 ↑ => osteoblastogenesis ↑ | Molagoda et al. [82] |
| Fisetin | In vitro | MC3T3-E1 mouse preosteoblasts | 0–800 nM, 12 d after 2 d of 20 µM prednisolone | Osteoblast-specific gene expression restored, anti-osteoblastic genes (NFATc1, ACP, DC-STAMP, cathepsin K) downregulated | Molagoda et al. [82] |
| Fisetin | In vivo | Zebrafish larvae 3 dpf | 50, 100, and 200 µM until 9 dpf | RUNX2a ↑, RUNX2b ↑, Col1α1 ↑, OSX ↑, OCN ↑, BMP4 ↑ => number of vertebrae ↑ | Molagoda et al. [82] |
| Clinical | |||||
| Dasatinib + quercetin, fisetin | In vivo | 120 females 70+ | Dasatinib+quercetin vs. fisetin p.o, intermittently, 20 w. | Ongoing (outcome measures: BTMs) | NCT04313634 |
ACP: acid phosphatase; ALP: alkaline phosphatase; BFR/BS: bone formation rate per bone surface; BMP4: bone morphogenic protein 4; BMSCs: bone marrow mesenchymal stem cells; BTMs: bone turnover markers; BV/TV: bone volume per tissue volume; CCR1: C-C chemokine receptor 1; c-FOS: key transcription factors; Col1α1: collagen type 1 alpha 1; CTR: calcitonin receptor; d: days; DC-STAMP: dendritic cell-specific transmembrane protein; dpf: days post-fertilization; FRT: focal radiation treatment; HPCs: hematopoietic progenitor cells; HSCs: hematopoietic stem cells; HUVECs: human umbilical vein epithelial cells; JNK: c-jun-N-terminal kinase; MKP-1: MAPK phosphatase 1; MMP9: matrix metalloproteinase 9; MSCs: mesenchymal stromal cells; NFATc1: nuclear factor of activated T cells 1; NF-kB: nuclear factor kB; NTX: N-telopeptide; Oc: osteoclast; OCN: osteocalcin; OSX: osterix; OVX: ovariectomy; p38 MAPK: p38 mitogen-activated protein kinase; PBMCs: peripheral blood mononuclear cells; RANKL: receptor activator nuclear factor kB; RUNX2: runt-related transcription factor 2; SABG: senescence-associated beta-galactosidase; SASP: senescence-associated secretory phenotype; TRAP: tartrate resistant acid phosphatase; w: weeks; ↓: decreased; ↑: increased; => leads to.