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Cited by 1,515Osteoarthritis Treatment and MechanismsTelomeres, Telomerase, and SenescenceGenetics, Aging, and Longevity in Model Organisms

Local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment

Open access
Jeon, Ok Hee, Kim, Chaekyu, Laberge, Remi-Martin, Demaria, Marco, Rathod, Sona, Vasserot, Alain P, Chung, Jae Wook, Kim, Do Hun +6 more·2017·Nature Medicine
DOI 10.1038/nm.4324PMC PMC5785239
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Abstract

Senescent cells (SnCs) accumulate in many vertebrate tissues with age and contribute to age-related pathologies, presumably through their secretion of factors contributing to the senescence-associated secretory phenotype (SASP). Removal of SnCs delays several pathologies and increases healthy lifespan. Aging and trauma are risk factors for the development of osteoarthritis (OA), a chronic disease characterized by degeneration of articular cartilage leading to pain and physical disability. Senescent chondrocytes are found in cartilage tissue isolated from patients undergoing joint replacement surgery, yet their role in disease pathogenesis is unknown. To test the idea that SnCs might play a causative role in OA, we used the p16-3MR transgenic mouse, which harbors a p16 INK4a (Cdkn2a) promoter driving the expression of a fusion protein containing synthetic Renilla luciferase and monomeric red fluorescent protein domains, as well as a truncated form of herpes simplex virus 1 thymidine kinase (HSV-TK). This mouse strain allowed us to selectively follow and remove SnCs after anterior cruciate ligament transection (ACLT). We found that SnCs accumulated in the articular cartilage and synovium after ACLT, and selective elimination of these cells attenuated the development of post-traumatic OA, reduced pain and increased cartilage development. Intra-articular injection of a senolytic molecule that selectively killed SnCs validated these results in transgenic, non-transgenic and aged mice. Selective removal of the SnCs from in vitro cultures of chondrocytes isolated from patients with OA undergoing total knee replacement decreased expression of senescent and inflammatory markers while also increasing expression of cartilage tissue extracellular matrix proteins. Collectively, these findings support the use of SnCs as a therapeutic target for treating degenerative joint disease.

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Crossref · 10.1038/nm.4324

Cites

40 of 40 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

34 of 48 cited sources checked · 18 supported · 1 flagged · accuracy not yet measured

  • Premisecitation

    UBX0101 was recently found to selectively eliminate senescent cells.

    “a senolytic (UBX0101) that was recently found to selectively eliminate SnCs16,29.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [16] Chang, J. et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med. 22, 78–83 (2016). source

      The Abstract identifies ABT263—not UBX0101—as the senolytic this study found to selectively kill senescent cells. A search of our copy for UBX0101 found no passage identifying it as a drug studied here. (LLM, conf=0.88)

      Checked by a reasoning model — may be wrong.

      Experimental — accuracy not yet measured
    • cites [29] Zhu, Y. et al. Identification of a novel senolytic agent, navitoclax, targeting the Bcl-2 family of anti-apoptotic factors. Aging Cell 15, 428–435 (2016). source

      The Results and Discussion describe navitoclax as a senolytic that selectively kills certain senescent cell types, but they do not address UBX0101. A search of our copy for UBX0101 found no passage identifying it or testing its effect on senescent cells; the navitoclax finding does not verify the claim about a different agent. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
  • Premisecitation

    The role of senescent chondrocytes in osteoarthritis pathogenesis is unknown.

    “yet their role in disease pathogenesis is unknown.”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [11] Martin, J.A., Brown, T., Heiner, A. & Buckwalter, J.A. Post-traumatic osteoarthritis: the role of accelerated chondrocyte senescence. Biorheology 41, 479–491 (2004). source
    • cites [12] Price, J.S. et al. The role of chondrocyte senescence in osteoarthritis. Aging Cell 1, 57–65 (2002). source
    • cites [13] Philipot, D. et al. p16INK4a and its regulator miR-24 link senescence and chondrocyte terminal differentiation–associated matrix remodeling in osteoarthritis. Arthritis Res. Ther. 16, R58 (2014). source

      The Introduction says it remains unclear how increased p16INK4a expression could contribute to osteoarthritis progression, supporting uncertainty about the mechanism. But it also describes deleterious effects of senescence-associated changes in chondrocytes, so saying their role in pathogenesis is wholly unknown overstates that uncertainty. The copy provides section labels but no page numbers. (LLM, conf=0.83)

      Experimental — accuracy not yet measured
    • cites [14] McCulloch, K., Litherland, G.J. & Rai, T.S. Cellular senescence in osteoarthritis pathology. Aging Cell 16, 210–218 (2017). source

      The Future perspectives section says the exact mechanism by which senescent chondrocytes contribute to osteoarthritis is not fully understood. But the section on senescence in OA chondrocytes and cartilage describes evidence for a pathological role, including cartilage damage after senescent-cell transplantation in mice. Saying their role is simply unknown overstates the paper's uncertainty; page numbers were not supplied. (LLM, conf=0.86)

      Experimental — accuracy not yet measured
  • Premisecitation

    The p16-3MR transgenic mouse harbors a p16INK4a promoter driving expression of a fusion protein containing Renilla luciferase and monomeric red fluorescent protein domains, as well as a truncated form of herpes simplex virus 1 thymidine kinase.

    “we used the p16-3MR transgenic mouse, which harbors a p16INK4a (Cdkn2a) promoter driving the expression of a fusion protein containing synthetic Renilla luciferase and monomeric red fluorescent protein domains, as well as a truncated form of herpes simplex virus 1 thymidine kinase (HSV-TK)15,16.”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [15] Demaria, M. et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell 31, 722–733 (2014). source
    • cites [16] Chang, J. et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med. 22, 78–83 (2016). source

      The passage labeled Abstract (page unavailable) describes p16-3MR mice as carrying a reporter driven by the Cdkn2a/p16 promoter and identifies Renilla luciferase, monomeric red fluorescent protein, and HSV-TK as its components. It does not specify that the luciferase is synthetic or that HSV-TK is truncated, so those details are not supported by our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
  • Premisecitation

    Senescent chondrocytes are found in cartilage tissue isolated from patients undergoing joint replacement surgery.

    “Senescent chondrocytes are found in cartilage tissue isolated from patients undergoing joint replacement surgery11–14”
    Quote in the paperSubstantial claim3 of 4 sources checked
    • cites [11] Martin, J.A., Brown, T., Heiner, A. & Buckwalter, J.A. Post-traumatic osteoarthritis: the role of accelerated chondrocyte senescence. Biorheology 41, 479–491 (2004). source
    • cites [12] Price, J.S. et al. The role of chondrocyte senescence in osteoarthritis. Aging Cell 1, 57–65 (2002). source
    • cites [13] Philipot, D. et al. p16INK4a and its regulator miR-24 link senescence and chondrocyte terminal differentiation–associated matrix remodeling in osteoarthritis. Arthritis Res. Ther. 16, R58 (2014). source
    • cites [14] McCulloch, K., Litherland, G.J. & Rai, T.S. Cellular senescence in osteoarthritis pathology. Aging Cell 16, 210–218 (2017). source

      The section ‘Senescence in OA chondrocytes & cartilage’ reports senescent cells in human osteoarthritic lesions and senescence-associated markers in OA chondrocytes. It does not say that the cartilage came from patients undergoing joint replacement surgery; no page number is available in our copy. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
  • Premisecitation

    Aging in mice contributes to the development of spontaneous and injury-induced osteoarthritis, similar to what occurs in humans.

    “Aging in mice contributes to the development of spontaneous and injury-induced OA, similar to what occurs in humans31,32.”
    Quote in the paperSubstantial claim1 of 2 sources checked
    • cites [31] Ruan, M.Z. et al. Proteoglycan 4 expression protects against the development of osteoarthritis. Sci. Transl. Med. 5, 176ra34 (2013). source
    • cites [32] Loeser, R.F. et al. Microarray analysis reveals age-related differences in gene expression during the development of osteoarthritis in mice. Arthritis Rheum. 64, 705–717 (2012). source
  • Classified as probably not a substantial claim. 26
  • May combine two claims. 46
  • The quote only partly states this claim. 2

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Senescent cells accumulate in many vertebrate tissues with age and contribute to age-related pathologies, presumably through their secretion of factors constituting the senescence-associated secretory phenotype.

    “Senescent cells (SnCs) accumulate in many vertebrate tissues with age and contribute to age-related pathologies1–3, presumably through their secretion of factors contributing to the senescence-associated secretory phenotype (SASP)4–6.”
    Quote in the paperSubstantial claim5 of 6 sources checked
    • cites [1] Campisi, J. Aging, cellular senescence, and cancer. Annu. Rev. Physiol. 75, 685–705 (2013). source
    • cites [2] van Deursen, J.M. The role of senescent cells in ageing. Nature 509, 439–446 (2014). source
    • cites [3] Campisi, J. Senescent cells, tumor suppression, and organismal aging: good citizens, bad neighbors. Cell 120, 513–522 (2005). source

      In “Cellular Senescence and Aging,” the paper says cells with characteristics of senescence accumulate with age in multiple human and rodent tissues. In “Bad Neighbors—Senescent Cells Alter Tissue Structure and Function,” it describes secreted factors as a plausible route to age-related pathology, but says senescent cells *might* contribute through this mechanism; the claim states their contribution to pathology more definitively. (LLM, conf=0.85)

      Experimental — accuracy not yet measured
    • cites [4] Coppé, J.P. et al. Senescence-associated secretory phenotypes reveal cell-nonautonomous functions of oncogenic RAS and the p53 tumor suppressor. PLoS Biol. 6, 2853–2868 (2008). source
    • cites [5] Campisi, J. Cancer, aging and cellular senescence. In Vivo 14, 183–188 (2000).
    • cites [6] Nelson, G. et al. A senescent cell bystander effect: senescence-induced senescence. Aging Cell 11, 345–349 (2012). source

      The Abstract says senescent cells secrete bioactive molecules and proposes that they may damage their surroundings or help drive aging. It does not establish that secreted SASP factors cause age-related pathologies; the bystander effect it demonstrates involves gap-junction contact and ROS. (LLM, conf=0.82)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    The superficial and deep cartilage layers interact to maintain homeostasis and increase new tissue production when needed.

    “the superficial and deep cartilage layers interact to maintain homeostasis and increase new tissue production when needed25”
    Quote in the paperNot a substantial claim1 of 1 sources checked
    • cites [25] Sharma, B. et al. Human cartilage repair with a photoreactive adhesive–hydrogel composite. Sci. Transl. Med. 5, 167ra6 (2013). source

      The Results section (‘Cartilage growth in hydrogels in vitro’; page unavailable) reports that chondrocytes cultured adjacent to mesenchymal stem cells increased cartilage-matrix production. But those were cell populations in a bilayered hydrogel, not the superficial and deep cartilage layers; the paper does not establish that those layers interact to maintain homeostasis or increase tissue production when needed. (LLM, conf=0.79)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Removal of senescent cells delays several pathologies and increases healthy lifespan.

    “Removal of SnCs delays several pathologies7–9 and increases healthy lifespan8.”
    Quote in the paperNot a substantial claim2 of 3 sources checked
    • cites [7] Baker, D.J. et al. Clearance of p16Ink4a-positive senescent cells delays ageing-associated disorders. Nature 479, 232–236 (2011). source
    • cites [8] Baker, D.J. et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016). source
    • cites [9] Baker, D.J. et al. Opposing roles for p16Ink4a and p19Arf in senescence and ageing caused by BubR1 insufficiency. Nat. Cell Biol. 10, 825–836 (2008). source

  • May combine two claims.

    Study design and conductcitation

    The p16-3MR mouse strain allows selective follow and removal of senescent cells after anterior cruciate ligament transection.

    “This mouse strain allowed us to selectively follow and remove SnCs after anterior cruciate ligament transection (ACLT).”
    Quote in the paperSubstantial claim2 of 2 sources checked
    • cites [15] Demaria, M. et al. An essential role for senescent cells in optimal wound healing through secretion of PDGF-AA. Dev. Cell 31, 722–733 (2014). source
    • cites [16] Chang, J. et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med. 22, 78–83 (2016). source

  • Classified as probably not a substantial claim.

    Premisecitation

    p16INK4a is a frequently used biomarker for senescent cells.

    “p16INK4a (also known as cyclin-dependent kinase inhibitor 2a; encoded by the Cdkn2a locus), a frequently used biomarker for SnCs8,17–19.”
    Quote in the paperSubstantial claim2 of 4 sources checked
    • cites [8] Baker, D.J. et al. Naturally occurring p16Ink4a-positive cells shorten healthy lifespan. Nature 530, 184–189 (2016). source
    • cites [17] Adams, P.D. Healing and hurting: molecular mechanisms, functions, and pathologies of cellular senescence. Mol. Cell 36, 2–14 (2009). source
    • cites [18] Sharpless, N.E. & Sherr, C.J. Forging a signature of in vivo senescence. Nat. Rev. Cancer 15, 397–408 (2015). source
    • cites [19] Ohtani, N., Yamakoshi, K., Takahashi, A. & Hara, E. The p16INK4a–RB pathway: molecular link between cellular senescence and tumor suppression. J. Med. Invest. 51, 146–153 (2004). source

      The p16INK4a-RB Pathway in Human Cancer (p. 4) says p16INK4a expression is low in normal proliferating cells and significantly induced during senescence, supporting its relevance as a senescence marker. The paper does not say that p16INK4a is frequently used as a biomarker. (LLM, conf=0.83)

      Experimental — accuracy not yet measured

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    HMGB1 is an extracellular alarmin whose nuclear expression precedes secretion of SASP components in cells undergoing senescence.

    “high-mobility-group box 1 (HMGB1)—an extracellular alarmin whose nuclear expression precedes the secretion of SASP components in cells undergoing senescence21,22.”
    Quote in the paperNot a substantial claim2 of 2 sources checked
    • cites [21] Holmlund, U. et al. The novel inflammatory cytokine high mobility group box protein 1 (HMGB1) is expressed by human term placenta. Immunology 122, 430–437 (2007). source

      The Introduction describes HMGB1 as a nuclear protein with extracellular inflammatory functions, and the Results report nuclear HMGB1 expression in placental cells. The paper does not address senescent cells, SASP components, or whether nuclear expression precedes their secretion; the Discussion says even HMGB1 secretion by the placental cells studied remains uncertain. Page numbers were not available in our copy. (LLM, conf=0.88)

      Experimental — accuracy not yet measured
    • cites [22] Davalos, A.R. et al. p53-dependent release of alarmin HMGB1 is a central mediator of senescent phenotypes. J. Cell Biol. 201, 613–629 (2013). source

      The Results section (‘Senescent human cells secrete HMGB1’) reports that HMGB1 moves from the nucleus to the extracellular space before SASP development. The distinction is that nuclear HMGB1 is lost—not newly expressed—before SASP components are secreted. (LLM, conf=0.84)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Premisecitation

    Age-related decline in proliferative and synthetic capacities of articular chondrocytes may reduce subsequent tissue regeneration.

    “the age-related decline in the proliferative and synthetic capacities of articular chondrocytes may reduce subsequent tissue regeneration33.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [33] Loeser, R.F. Aging and osteoarthritis: the role of chondrocyte senescence and aging changes in the cartilage matrix. Osteoarthritis Cartilage 17, 971–979 (2009). source

  • May combine two claims.

    Interpretationown data

    GCV may not reach the bone when injected intra-articularly, and systemic administration may be required.

    “suggesting that GCV may not reach the bone when injected intra-articularly and that systemic administration may be required16.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [16] Chang, J. et al. Clearance of senescent cells by ABT263 rejuvenates aged hematopoietic stem cells in mice. Nat. Med. 22, 78–83 (2016). source

      The Online Methods (page unavailable) report that GCV was given by intraperitoneal injection, and the results passage reports depletion of senescent cells in irradiated mice. The paper does not examine intra-articular injection or whether GCV reaches bone by that route, so it does not establish that systemic administration may be required. (LLM, conf=0.78)

      Experimental — accuracy not yet measured
    • Rests on an assumption: ACLT in mice is a valid model of post-traumatic osteoarthritis.

  • May combine two claims.

    Interpretationcitation

    UBX0101 can clear senescent cells from aged articular cartilage, but age-related decline in proliferative and synthetic capacities of articular chondrocytes may reduce subsequent tissue regeneration.

    “These findings suggest that UBX0101 can clear SnCs from aged articular cartilage, but the age-related decline in the proliferative and synthetic capacities of articular chondrocytes may reduce subsequent tissue regeneration33.”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [33] Loeser, R.F. Aging and osteoarthritis: the role of chondrocyte senescence and aging changes in the cartilage matrix. Osteoarthritis Cartilage 17, 971–979 (2009). source
    • Rests on an assumption: ACLT in mice is a valid model of post-traumatic osteoarthritis.

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    The 3D pellet culture system supports maintenance of chondrocyte phenotype and chondrogenesis.

    “a 3D pellet culture system that supports maintenance of the chondrocyte phenotype and chondrogenesis”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [34] Sekiya, I., Vuoristo, J.T., Larson, B.L. & Prockop, D.J. In vitro cartilage formation by human adult stem cells from bone marrow stroma defines the sequence of cellular and molecular events during chondrogenesis. Proc. Natl. Acad. Sci. USA 99, 4397–4402 (2002). source

      The Methods describe a pellet culture of marrow stromal cells, and the Results report cartilage-matrix synthesis as those cells differentiated into chondrocytes. The paper supports chondrogenesis in this system, but it does not establish that the system maintains the phenotype of existing chondrocytes. (LLM, conf=0.88)

      Experimental — accuracy not yet measured

  • Classified as probably not a substantial claim.

    Study design and conductcitation

    Histological assessment of the medial tibial plateau joint was performed through blinded graded observations by two observers following OARSI scoring.

    “histological assessment of the medial tibial plateau joint through blinded graded observations by two observers who followed the Osteoarthritis Research Society International (OARSI) scoring system35”
    Quote in the paperSubstantial claim1 of 1 sources checked
    • cites [35] Glasson, S.S., Chambers, M.G., Van Den Berg, W.B. & Little, C.B. The OARSI histopathology initiative—recommendations for histological assessments of osteoarthritis in the mouse. Osteoarthritis Cartilage 18 (Suppl. 3), S17–S23 (2010). source

  • May combine two claims.

    Findingown data

    ACLT surgery caused decreased weight bearing on the injured leg and an increased latency period for the injured hindlimb to reach a pain threshold.

    “Behavioral assessment of OA-induced pain showed that ACLT surgery caused decreased weight bearing on the injured leg and an increased latency period required for the injured hindlimb to reach a pain threshold after the mouse was placed on a 55 °C platform”
    Quote in the paperSubstantial claim
    • Rests on an assumption: ACLT in mice is a valid model of post-traumatic osteoarthritis.

  • May combine two claims.

    Findingown data

    Both five and six injections of 1 mM UBX0101 resulted in lower expression of Cdkn2a, Mmp13 and Il1b, higher expression of Col2a1 and Acan, and less OA-induced pain compared to vehicle-treated ACLT mice.

    “Both five and six injections of 1 mM UBX0101 resulted in lower expression of Cdkn2a, Mmp13 and Il1b, higher expression of Col2a1 and Acan, and less OA-induced pain in comparison to vehicle-treated ACLT mice.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: ACLT in mice is a valid model of post-traumatic osteoarthritis.

  • May combine two claims.

    Findingown data

    In sham-operated controls, there were fewer cells positive for p16INK4a staining and HMGB1 was largely nuclear.

    “In contrast, in sham-operated controls, there were fewer cells positive for p16INK4a staining and HMGB1 was largely nuclear.”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: ACLT in mice is a valid model of post-traumatic osteoarthritis.

  • May combine two claims.

    Findingown data

    The half-life of UBX0101 in the articular joint was short, with concentrations falling below IC50 after 1.5 hours.

    “The half-life of UBX0101 in the articular joint was short, with concentrations falling below the half-maximal inhibitory concentration (IC50) after 1.5 h.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Reduction of proteoglycan and OA-related pain was maintained between 28 and 56 days after surgery, and gene and protein levels of Col2a1 and Acan remained upregulated compared to untreated controls.

    “Reduction of proteoglycan and OA-related pain was maintained between 28 and 56 d after surgery and the gene and protein levels of the prochondrogenic factors Col2a1 and Acan remained upregulated in comparison to the untreated controls”
    Quote in the paperSubstantial claim
    • Rests on an assumption: ACLT in mice is a valid model of post-traumatic osteoarthritis.

  • May combine two claims.

    Findingown data

    In vehicle-treated ACLT mice, p16INK4a protein was largely restricted to the superficial zone, where 66% of cells were positive for p16INK4a, and 65% of cells had little to no nuclear HMGB1 staining in articular cartilage.

    “In vehicle-treated ACLT mice, p16INK4a protein was largely restricted to the superficial zone, where 66% of cells were positive for p16INK4a, and 65% of cells had little to no nuclear HMGB1 staining in articular cartilage”
    Quote in the paperSubstantial claim
    • Rests on an assumption: ACLT in mice is a valid model of post-traumatic osteoarthritis.

  • May combine two claims.

    Findingown data

    Clearance was confirmed by reduced injury-induced increases in mRNA levels of Cdkn2a and Cdkn1a, increased immunostaining for nuclear HMGB1, and reduced p16INK4a protein in cartilage.

    “Clearance was confirmed by reduced injury-induced increases in the mRNA levels of Cdkn2a and Cdkn1a (Fig. 1c,d), along with increased immunostaining for nuclear HMGB1 and reduced p16INK4a protein in the cartilage (Fig. 1e,f).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: ACLT in mice is a valid model of post-traumatic osteoarthritis.

  • May combine two claims.

    Findingown data

    Systemic exposure was minimal (3.3% of intra-articular dose reached circulation), and IC50 was never reached.

    “Systemic exposure was minimal (3.3% of the intra-articular dose reached the circulation), and the IC50 was never reached”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    UBX0101 treatment decreased luciferase signal and reduced expression of Cdkn2a, Cdkn1a, Mmp13 and Il1b (up to 50% reduction).

    “The luciferase signal decreased after UBX0101 treatment (Supplementary Fig. 3a), and SnC clearance was confirmed by reduced expression of Cdkn2a, Cdkn1a, Mmp13 and Il1b (up to a 50% reduction) in UBX0101-treated ACLT mice”
    Quote in the paperSubstantial claim
    • Rests on an assumption: ACLT in mice is a valid model of post-traumatic osteoarthritis.

  • May combine two claims.

    Findingown data

    Pathological changes in subchondral bone and increased expression of bone-resorption-related genes after ACLT were not rescued by GCV treatment.

    “there were pathological changes in the structure and/or appearance of the subchondral bone and the expression of bone-resorption-related genes28 was increased after ACLT surgery and OA development; these phenotypes were not rescued by GCV treatment”
    Quote in the paperSubstantial claim
    • Rests on an assumption: ACLT in mice is a valid model of post-traumatic osteoarthritis.

  • May combine two claims.

    Findingown data

    Fewer Ki-67-expressing cells were observed in the synovium of vehicle-treated C57BL mice, consistent with presence of synovial senescent cells, which was abrogated by UBX0101 treatment.

    “We also observed fewer Ki-67-expressing cells in the synovium of vehicle-treated C57BL mice, a finding consistent with the presence of synovial SnCs, which was abrogated by UBX0101 treatment”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: ACLT in mice is a valid model of post-traumatic osteoarthritis.

  • May combine two claims.

    Findingown data

    ACLT-mediated injury reduced safranin O staining of proteoglycans and resulted in cartilage thinning, surface irregularities and induction of type II collagen degradation.

    “ACLT-mediated injury reduced safranin O staining of proteoglycans and resulted in cartilage thinning, surface irregularities and induction of type II collagen degradation”
    Quote in the paperSubstantial claim
    • Rests on an assumption: ACLT in mice is a valid model of post-traumatic osteoarthritis.

  • May combine two claims. The quote only partly states this claim.

    Findingown data

    Senescent cell removal increases cartilage development, as shown by increased protein and mRNA levels of Col2a1 and Acan.

    “SnC removal increased the protein and mRNA levels of Col2a1 and Acan (corresponding to the cartilage extracellular matrix molecules type II collagen and aggrecan, respectively).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: ACLT in mice is a valid model of post-traumatic osteoarthritis.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Findingown data

    Nuclear HMGB1 staining differed little to none between OA tissues and healthy controls.

    “there was little to no difference in nuclear HMGB1 staining in OA tissues as compared to tissues from healthy controls”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    In human OA chondrocyte cultures, 43 μM UBX0101 for 2 d killed 20% of senescent cells and no more than 5% of non-senescent cells.

    “this regimen killed 20% of the SnCs and no more than 5% of non-SnCs”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Distribution of senescent cells in aged mice after ACLT was different from young mice; 40% of p16INK4a-positive senescent cells were localized throughout the articular cartilage instead of only in the superficial layer.

    “the distribution of the SnCs in aged mice after ACLT was different from that in young mice after ACLT. In particular, 40% of p16INK4a-positive SnCs were localized throughout the articular cartilage of vehicle-treated ACLT mice instead of only in the superficial layer”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: ACLT in mice is a valid model of post-traumatic osteoarthritis.

  • May combine two claims.

    Findingown data

    ACLT mice treated with UBX0101 had a reduction in subchondral bone sclerosis but similar osteophyte formation relative to vehicle-treated controls.

    “ACLT mice treated with UBX0101 had a reduction in subchondral bone sclerosis but similar osteophyte formation relative to vehicle-treated controls”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: ACLT in mice is a valid model of post-traumatic osteoarthritis.

  • May combine two claims.

    Findingown data

    In pellet cultures, UBX0101 lowered mRNA for CDKN2A, MMP3, IL1B, and IL6 while raising COL2A1 and ACAN mRNA.

    “UBX0101 also reduced CDKN2A, MMP3, IL1B and IL6 mRNA levels and increased COL2A1 and ACAN mRNA levels”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    After injury, older mice showed greater senescence burden and more severe OA than younger mice.

    “Aged mice had a higher senescence burden and developed more severe OA after injury”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The data had normal variance.

  • May combine two claims.

    Findingown data

    UBX0101 decreased p16INK4a and MMP13 protein levels and increased COL2A1, proteoglycan, and sGAG levels in pellet cultures.

    “UBX0101 decreased p16INK4a and MMP13 protein levels and increased the levels of COL2A1, proteoglycan and sulfated glycosaminoglycans (sGAGs)”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Baseline morphology of aged animals without surgery showed thinning cartilage with reduced safranin O staining and higher OARSI scores.

    “The baseline morphology of the aged animals without surgery showed thinning cartilage with reduced safranin O staining for proteoglycans and higher OARSI scores.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Findingown data

    Histologically, there was a small increase in safranin O staining in ACLT mice treated with UBX0101, but OARSI scores were not significantly lower than vehicle-treated ACLT mice, given small number of animals.

    “Histologically, there was a small increase in safranin O staining of the articular cartilage in ACLT mice treated with UBX0101, but the OARSI scores were not significantly lower than those of the vehicle-treated ACLT mice, given the small number of animals in this study”
    Quote in the paperNot a substantial claim
    • Rests on an assumption: ACLT in mice is a valid model of post-traumatic osteoarthritis.

  • May combine two claims.

    Findingown data

    Selective removal of senescent cells from in vitro cultures of chondrocytes isolated from patients with osteoarthritis undergoing total knee replacement decreased expression of senescent and inflammatory markers while increasing expression of cartilage tissue extracellular matrix proteins.

    “Selective removal of the SnCs from in vitro cultures of chondrocytes isolated from patients with OA undergoing total knee replacement decreased expression of senescent and inflammatory markers while also increasing expression of cartilage tissue extracellular matrix proteins.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    UBX0101 treatment increased activated caspase-3 levels in human OA chondrocytes but not healthy chondrocytes.

    “Increased levels of activated caspase-3 suggest that UBX0101 kills SnCs through the apoptotic pathway in treated human OA chondrocytes (but not healthy chondrocytes”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    UBX0101 treatment increased the number of non-senescent cells with nuclear HMGB1, reduced OA-induced pain, and reduced levels of Cdkn2a, Cdkn1a and Mmp13 mRNAs in mice injected 42 days after ACLT.

    “UBX0101 treatment increased the number of non-SnCs with nuclear HMGB1 (Supplementary Fig. 9b), reduced OA-induced pain (Supplementary Fig. 9c) and reduced the levels of Cdkn2a, Cdkn1a and Mmp13 mRNAs (Supplementary Fig. 9d).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: ACLT in mice is a valid model of post-traumatic osteoarthritis.

  • May combine two claims.

    Findingown data

    Osteoarthritis disease (cartilage degradation and subchondral bone sclerosis) and OA-induced pain returned at 84 days after ACLT or 4 weeks after last drug injection.

    “OA disease (cartilage degradation and subchondral bone sclerosis) and OA-induced pain returned at 84 d after ACLT or 4 weeks after the last drug injection”
    Quote in the paperSubstantial claim
    • Rests on an assumption: ACLT in mice is a valid model of post-traumatic osteoarthritis.

  • May combine two claims.

    Findingown data

    Senescent cells in synovium were cleared with UBX0101 treatment, and those in subchondral bone marrow were slightly reduced in number.

    “SnCs found in the synovium were cleared with UBX0101 treatment, and those in the subchondral bone marrow were slightly reduced in number”
    Quote in the paperSubstantial claim
    • Rests on an assumption: ACLT in mice is a valid model of post-traumatic osteoarthritis.

  • May combine two claims.

    Findingown data

    Removal of senescent cells via transgenic mouse models or pharmaceutical intervention reduced development of post-traumatic OA and related pain and created a prochondrogenic environment.

    “The removal of SnCs, through transgenic mouse models or pharmaceutical intervention, reduced the development of post-traumatic OA and related pain and created a prochondrogenic environment”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The data had normal variance.

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    The role of the synovium in osteoarthritis has long been postulated.

    “The role of the synovium in OA has long been postulated23”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Sellam, J. & Berenbaum, F. The role of synovitis in pathophysiology and clinical symptoms of osteoarthritis. Nat. Rev. Rheumatol. 6, 625–635 (2010). source

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    Aging and trauma are risk factors for the development of osteoarthritis.

    “Aging and trauma are risk factors for the development of osteoarthritis (OA)10”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [10] Wieland, H.A., Michaelis, M., Kirschbaum, B.J. & Rudolphi, K.A. Osteoarthritis—an untreatable disease? Nat. Rev. Drug Discov. 4, 331–344 (2005). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Mmp13 and Il-1β expression is typical of osteoarthritis disease and tissue degradation.

    “the inflammatory markers matrix metalloproteinase 13 (Mmp13) and Il-1β (Il1b) (Fig. 1d), whose expression is typical of OA disease and tissue degradation27”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [27] Goldring, M.B. & Otero, M. Inflammation in osteoarthritis. Curr. Opin. Rheumatol. 23, 471–478 (2011). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Osteoarthritis is a chronic disease characterized by degeneration of articular cartilage leading to pain and physical disability.

    “a chronic disease characterized by degeneration of articular cartilage leading to pain and physical disability.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Wieland, H.A., Michaelis, M., Kirschbaum, B.J. & Rudolphi, K.A. Osteoarthritis—an untreatable disease? Nat. Rev. Drug Discov. 4, 331–344 (2005). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    Runx2 is a regulator of chondrocyte hypertrophy and bone development.

    “Runx2, a regulator of chondrocyte hypertrophy and bone development30”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Komori, T. Signaling networks in RUNX2-dependent bone development. J. Cell. Biochem. 112, 750–755 (2011). source

  • Classified as probably not a substantial claim.

    Premisecitation

    Purported cartilage progenitor cells are located in the superficial layer of cartilage.

    “this is where purported cartilage progenitor cells are located24.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [24] Dowthwaite, G.P. et al. The surface of articular cartilage contains a progenitor cell population. J. Cell Sci. 117, 889–897 (2004). source

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    No samples or animals were excluded from analysis except mice that died early from fighting.

    “No samples or animals were excluded from the analysis except mice who died early as a result of fighting”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductown data

    Pilot experiments were performed to determine average and s.d., and a power analysis was performed to determine adequate animal numbers.

    “Pilot experiments were performed with a small number of animals (Supplementary Fig. 1) to determine average and s.d. in the model and characterization methods. From this information, a power analysis was performed to determine adequate animal numbers to achieve statistical significance.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    Senescent cells develop after trauma in the articular cartilage and synovium of the knee joint, and their removal, even after osteoarthritis and symptoms develop, reduces disease impact and creates a prochondrogenic environment.

    “Together, these data suggest that SnCs develop after trauma in the articular cartilage and synovium of the knee joint and their removal, even after OA and symptoms develop, reduces disease impact and creates a prochondrogenic environment.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: ACLT in mice is a valid model of post-traumatic osteoarthritis.

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    Human articular cartilage samples were obtained according to an IRB-approved protocol, and patients gave informed consent.

    “Human articular cartilage samples explanted from patients with OA undergoing total knee arthroplasty were received from the National Disease Resource Institution (Philadelphia, PA, USA) according to an IRB-approved protocol. Patients in the registry in NDRI (National Disease Research Interchange) gave informed consent for the donation of organs and tissues for research and education.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Study design and conductnone given

    The experimental protocol was approved by and performed in accordance with IACUC protocols at Johns Hopkins University and the Mayo Clinic.

    “The experimental protocol was approved by and performed in accordance with protocols from the Institutional Animal Care and Use Committee at Johns Hopkins University and the Mayo Clinic Institutional Animal Care and Use Committee.”
    Quote in the paperNot a substantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Study design and conductnone given

    Mice used for all experiments were randomly assigned to control or treatment groups and to OA evaluation.

    “The mice used for all experiments were randomly assigned to control or treatment groups and to those used in OA evaluation.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable). May combine two claims.

    Interpretationreasoning

    Additional treatments, and potentially systemic treatment, might be required to reduce disease and rebuild cartilage tissue in older animals with naturally occurring osteoarthritis.

    “it is likely that additional treatments, and potentially systemic treatment, might be required to reduce disease and rebuild cartilage tissue.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    In human OA chondrocytes, UBX0101 induces senescent cell death via apoptosis, whereas healthy chondrocytes are not killed this way.

    “UBX0101 kills SnCs through the apoptotic pathway in treated human OA chondrocytes (but not healthy chondrocytes”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductown data

    Sample size was not predetermined by any statistical method.

    “No statistical method was used to predetermine sample size.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    UBX0101 was effective in blocking cartilage erosion in the ACLT mouse model because it eliminated senescent cells rather than blocking their SASP secretion.

    “UBX0101 was effective in blocking cartilage erosion in our ACLT mouse model because UBX0101 eliminated SnCs rather than blocking their SASP secretion.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: ACLT in mice is a valid model of post-traumatic osteoarthritis.

  • Classified as probably not a substantial claim. May combine two claims.

    Interpretationreasoning

    In mouse ACLT surgery, the ligament cannot be repaired, so continued damage may occur in the joint in addition to age-related accumulation of senescent cells over time.

    “In mouse ACLT surgery, the ligament cannot be repaired, so continued damage may occur in the joint in addition to age-related accumulation of SnCs over time.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: In mouse ACLT surgery, the ligament cannot be repaired.

  • Probably not a substantial claim: may not pass S1 (asserted), S3 (load-bearing), S4 (based). The quote only partly states this claim.

    Study design and conductnone given

    In weight bearing, the observer was blinded to genotype and treatment.

    “The observer was blinded to the genotype and treatment of the mice.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    In hotplate analysis, the observer was blinded to genotype and treatment.

    “The observer was blinded to the genotype and treatment of the mice.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Study design and conductnone given

    The experiments were not randomized, except for in vivo animal studies.

    “The experiments were not randomized, except for the in vivo animal studies with mice, as described above.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationown data

    UBX0101 can clear senescent cells from articular cartilage to reduce osteoarthritis symptoms and modify the disease by creating a pro-regenerative environment even in later-stage disease.

    “Together, these results indicate that UBX0101 can clear SnCs from articular cartilage to reduce OA symptoms and modify the disease by creating a pro-regenerative environment even in later-stage disease.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: ACLT in mice is a valid model of post-traumatic osteoarthritis.
60 of 60

  • The paper relies on this without support.

    ACLT in mice is a valid model of post-traumatic osteoarthritis.

    “We induced post-traumatic OA by ACLT in p16-3MR transgenic mice”

  • The paper relies on this without support.

    In mouse ACLT surgery, the ligament cannot be repaired.

    “In mouse ACLT surgery, the ligament cannot be repaired”

  • The paper relies on this without support.

    The data had normal variance.

    “The data displayed normal variance.”

  • The paper relies on this without support.

    Human OA chondrocytes isolated from patients undergoing total knee arthroplasty are representative of clinical OA.

    “The relevance of SnCs and their clearance in clinical OA was evaluated in explant and in vitro cultures from patients undergoing total knee arthroplasty.”
    “The relevance of our findings to human disease was validated using chondrocytes isolated from arthritic patients.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Killing p16-positive cells in transgenic mice reduces age-related disease and lengthens health span in two independent mouse strains, INK-ATTAC and p16-3MR.

    “Ablating p16+ cells in these mice suppresses age-related disease, extending the health span of two independent strains of transgenic mice: INK-ATTAC and p16-3MR (see Supplemental Figure 1 for a description of the models) (8–10).”

    From Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span (2021) · cites this paper as [10]

    The main text (Fig. 3a–c) reports that clearing p16-positive cells in INK-ATTAC mice reduced age-related cartilage degeneration. It also reports reduced post-traumatic osteoarthritis symptoms in p16-3MR mice (Fig. 1), but does not show extended health span in both strains; its statement about increased healthy lifespan cites earlier work. (LLM, conf=0.88)

    Experimental — accuracy not yet measured

  • Navitoclax treatment in mice lowers senescent cell burden, improves radiation-induced hematopoietic stem cell dysfunction, and alleviates osteoarthritis.

    “Treating mice with navitoclax reduces Snc burden, alleviates radiation-induced hematopoietic stem cell dysfunction (28), and improves osteoarthritis (10).”

    From Senolytic Drugs: Reducing Senescent Cell Viability to Extend Health Span (2021) · cites this paper as [10]

    The paper’s osteoarthritis results (Fig. 2 and Supplementary Fig. 3; page unavailable) report reduced senescent cells, pain, and cartilage erosion in mice treated with UBX0101. The Online Methods list UBX0101, ganciclovir, and AP20187 as treatments, not navitoclax, so this source does not support attributing the osteoarthritis improvement to navitoclax. The radiation-induced stem-cell claim is attached to citation (28), not this source’s citation (10). (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • Phenotypic drug screens have identified heat-shock protein inhibitors, cardiac glycosides, and p53-MDM2 interaction inhibitors as having senolytic activity.

    “Phenotypic drug screens have pinpointed compounds as varied as heat-shock protein inhibitors (Fuhrmann-Stroissnigg et al. 2017), cardiac glycosides (Guerrero et al. 2019; Triana-Martínez et al. 2019), and p53–MDM2 interaction inhibitors (Jeon et al. 2017) as harboring senolytic activity.”

    From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Jeon et al. 2017

    The paper’s results report that preliminary screening found UBX0101 killed senescent human osteoarthritis chondrocytes (Supplementary Fig. 12), supporting its senolytic activity. Our copy does not identify UBX0101 as a p53–MDM2 interaction inhibitor, so it does not substantiate the drug-class attribution attached to Jeon et al. The heat-shock protein inhibitors and cardiac glycosides are attributed to other citations in the sentence. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Cellular senescence encompasses heterogeneous cellular states triggered by prolonged cell stress resulting in irreversible arrest of proliferation and permanent changes to cell function in vivo.

    “Cellular senescence, a central hallmark of aging,13,14 encompasses heterogeneous cellular states triggered by prolonged cell stress resulting in the irreversible arrest of proliferation and permanent changes to cell function in vivo.15,16,17,18,19”

    From Uncovering the signatures of aging and senescence in the human dorsolateral prefrontal cortex (2026) · cites this paper as [19]

    The paper’s Abstract and main text report senescent cells accumulating with age and developing after joint injury, with altered secretory markers and evidence of reduced proliferation. They do not establish that senescence comprises heterogeneous cellular states, requires prolonged stress, or entails irreversible proliferation arrest and permanent functional changes in vivo. Page numbers are unavailable in our copy. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

  • Removing senescent cells reduces post-traumatic and naturally occurring osteoarthritis in mouse models.

    “removal of senescent cells reduced the development of post-traumatic and naturally occurring osteoarthritis in mouse models121”

    From Telomere dysfunction in ageing and age-related diseases (2022) · cites this paper as [121]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Time since the final injection is misstated

    Minor

    Six injections every two days starting on day 14 place the final injection around day 24. Day 84 is therefore about 60 days after the final injection, not four weeks; this changes the reported duration of the treatment effect.

  • Maximum animal exclusion conflicts with the stated exclusions

    Minor

    The statistics section says that one or two animals were excluded per experiment, but then says the maximum was one animal out of 40. An experiment with two exclusions would exceed that stated maximum.

  • Pellet harvest timing conflicts with the treatment schedule

    Minor

    The methods say pellets were harvested after 21 days, while the results describe treating pellets for four days after 21 days of growth. Those treated pellets could not have been harvested at day 21.

3 of 3

Cites

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Related

Authors
Jeon, O. H., Kim, C., Laberge, R.-M., Demaria, M., Rathod, S., Vasserot, A. P., Chung, J. W., Kim, D. H., Poon, Y., David, N., Baker, D. J., van Deursen, J. M., Campisi, J., & Elisseeff, J. H.
Affiliations
  • Johns Hopkins University (US)
  • University Medical Center Groningen (NL)
  • Unity Biotechnology (United States) (US)
  • Mayo Clinic (US)
  • Buck Institute for Research on Aging (US)
Corresponding author
Elisseeff, Jennifer H
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
2017-04-24
Volume
23
Issue
6
Pages
775-781
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm.4324
PMC
PMC5785239
OpenAlex
W2608899726
Semantic Scholar
53c54ba96c49cd92f21d4da0aa26a80dd0322f36
Cited by
1,515
References
39
Citations by year
2026: 132 · 2025: 170 · 2024: 168 · 2023: 197 · 2022: 192 · 2021: 193 · 2020: 180 · 2019: 143 · 2018: 106 · 2017: 32
FWCI
110.18
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • University of Groningen research database (University of Groningen / Centre for Information Technology) (submittedVersion, other-oa)
  • Radboud Repository (Radboud University) (submittedVersion)
  • Scholarworks@UNIST (Ulsan National Institute of Science and Technology) (submittedVersion)
Funders
  • National Institute on Aging (R56AG009909, R37AG009909, P01AG017242)
  • National Cancer Institute (R01CA096985)
Topics
  • Health Sciences › Medicine › Rheumatology › Osteoarthritis Treatment and Mechanisms
  • Health Sciences › Medicine › Physiology › Telomeres, Telomerase, and Senescence
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Aging › Genetics, Aging, and Longevity in Model Organisms
Keywords
senolytics, senescent cells, post-traumatic osteoarthritis, chondrocytes, articular cartilage degeneration, senescence-associated secretory phenotype, anterior cruciate ligament transection, p16INK4a, HSV-TK, cartilage matrix, synovium, osteoarthritis
MeSH terms
Anterior Cruciate Ligament Injuries, Animals, Antiviral Agents, Cartilage, Articular, Fluorescent Antibody Technique, Glycosaminoglycans, Humans, Immunohistochemistry, Mice, Transgenic, Regeneration, Immunoblotting, Ganciclovir, Anterior Cruciate Ligament, Extracellular Matrix Proteins, Weight-Bearing, Cellular Senescence, Chondrocytes, Cyclin-Dependent Kinase Inhibitor p16, Reverse Transcriptase Polymerase Chain Reaction, Osteoarthritis, Knee, Mice, Real-Time Polymerase Chain Reaction, In Vitro Techniques

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read under definition version 3 (extract-v3) on 2026-09-28.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-09-28.

Cited sources are checked by gpt-6-sol.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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