Skip to main content
Log in

Stem cells in degenerative orthopaedic pathologies: effects of aging on therapeutic potential

  • Experimental Study
  • Published:
Knee Surgery, Sports Traumatology, Arthroscopy Aims and scope

    We’re sorry, something doesn't seem to be working properly.

    Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Abstract

Purpose

The purpose of this study was to summarize the current evidence on the use of stem cells in the elderly population with degenerative orthopaedic pathologies and to highlight the pathophysiologic mechanisms behind today’s therapeutic challenges in stem cell-based regeneration of destructed tissues in the elderly patients with osteoarthritis (OA), degenerative disc disease (DDD), and tendinopathies.

Methods

Clinical and basic science studies that report the use of stem cells in the elderly patients with OA, DDD, and tendinopathies were identified using a PubMed search. The studies published in English have been assessed, and the best and most recent evidence was included in the current study.

Results

Evidence suggests that, although short-term results regarding the effects of stem cell therapy in degenerative orthopaedic pathologies can be promising, stem cell therapies do not appear to reverse age-related tissue degeneration. Causes of suboptimal outcomes can be attributed to the decrease in the therapeutic potential of aged stem cell populations and the regenerative capacity of these cells, which might be negatively influenced in an aged microenvironment within the degenerated tissues of elderly patients with OA, DDD, and tendinopathies.

Conclusions

Clinical protocols guiding the use of stem cells in the elderly patient population are still under development, and high-level randomized controlled trials with long-term outcomes are lacking. Understanding the consequences of age-related changes in stem cell function and responsiveness of the in vivo microenvironment to stem cells is critical when designing cell-based therapies for elderly patients with degenerative orthopaedic pathologies.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Al Faqeh H, Nor Hamdan BM, Chen HC, Aminuddin BS, Ruszymah BH (2012) The potential of intra-articular injection of chondrogenic-induced bone marrow stem cells to retard the progression of osteoarthritis in a sheep model. Exp Gerontol 47:458–464

    Article  PubMed  Google Scholar 

  2. Ando W, Heard BJ, Chung M, Nakamura N, Frank CB, Hart DA (2012) Ovine synovial membrane-derived mesenchymal progenitor cells retain the phenotype of the original tissue that was exposed to in vivo inflammation: evidence for a suppressed chondrogenic differentiation potential of the cells. Inflamm Res 61:599–608

    Article  CAS  PubMed  Google Scholar 

  3. Avery NC, Bailey AJ (2005) Enzymic and non-enzymic cross-linking mechanisms in relation to turnover of collagen: relevance to aging and exercise. Scand J Med Sci Sports 15:231–240

    Article  CAS  PubMed  Google Scholar 

  4. Badowski M, Muise A, Harris DT (2014) Mixed effects of long-term frozen storage on cord tissue stem cells. Cytotherapy 16:1313–1321

    Article  CAS  PubMed  Google Scholar 

  5. Beane OS, Fonseca VC, Cooper LL, Koren G, Darling EM (2014) Impact of aging on the regenerative properties of bone marrow-, muscle-, and adipose-derived mesenchymal stem/stromal cells. PLoS ONE 9:e115963

    Article  PubMed  PubMed Central  Google Scholar 

  6. Bogdanova A, Berzins U, Nikulshin S, Skrastina D, Ezerta A, Legzdina D, Kozlovska T (2014) Characterization of human adipose-derived stem cells cultured in autologous serum after subsequent passaging and long term cryopreservation. J Stem Cells. 9:135–148

    PubMed  Google Scholar 

  7. Centeno CJ, Schultz JR, Cheever M, Freeman M, Faulkner S, Robinson B, Hanson R (2011) Safety and complications reporting update on the re-implantation of culture-expanded mesenchymal stem cells using autologous platelet lysate technique. Curr Stem Cell Res Ther 6:368–378

    Article  CAS  PubMed  Google Scholar 

  8. Chatterjea A, LaPointe VL, Alblas J, Chatterjea S, van Blitterswijk CA, de Boer J (2014) Suppression of the immune system as a critical step for bone formation from allogeneic osteoprogenitors implanted in rats. J Cell Mol Med 18:134–142

    Article  CAS  PubMed  Google Scholar 

  9. Chen B, Deng Y, Tan Y, Qin J, Chen LB (2014) Association between severity of knee osteoarthritis and serum and synovial fluid interleukin 17 concentrations. J Int Med Res 42:138–144

    Article  PubMed  Google Scholar 

  10. Clayton RA, Court-Brown CM (2008) The epidemiology of musculoskeletal tendinous and ligamentous injuries. Injury 39:1338–1344

    Article  PubMed  Google Scholar 

  11. De Miguel MP, Fuentes-Julián S, Blázquez-Martínez A, Pascual CY, Aller MA, Arias J, Arnalich-Montiel F (2012) Immunosuppressive properties of mesenchymal stem cells: advances and applications. Curr Mol Med 12:574–591

    Article  PubMed  Google Scholar 

  12. Diekman BO, Guilak F (2013) Stem cell-based therapies for osteoarthritis: challenges and opportunities. Curr Opin Rheumatol 25:119–126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Emadedin M, Aghdami N, Taghiyar L, Fazeli R, Moghadasali R, Jahangir S, Farjad R, Baghaban Eslaminejad M (2012) Intra-articular injection of autologous mesenchymal stem cells in six patients with knee osteoarthritis. Arch Iran Med 15:422–428

    PubMed  Google Scholar 

  14. Fernyhough LJ, Buchan VA, McArthur LT, Hock BD (2013) Relative recovery of haematopoietic stem cell products after cryogenic storage of up to 19 years. Bone Marrow Transpl 48:32–35

    Article  CAS  Google Scholar 

  15. Goldring MB, Otero M (2011) Inflammation in osteoarthritis. Curr Opin Rheumatol 23:471–478

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gupta PK, Das AK, Chullikana A, Majumdar AS (2012) Mesenchymal stem cells for cartilage repair in osteoarthritis. Stem Cell Res Ther 3:25

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Hauser RA, Orlofsky A (2013) Regenerative injection therapy with whole bone marrow aspirate for degenerative joint disease: a case series. Clin Med Insights Arthritis Musculoskelet Disord 6:65–72

    PubMed  PubMed Central  Google Scholar 

  18. Heldens GT, Blaney Davidson EN, Vitters EL, Schreurs BW, Piek E, van den Berg WB, van der Kraan PM (2012) Catabolic factors and osteoarthritis-conditioned medium inhibit chondrogenesis of human mesenchymal stem cells. Tissue Eng Part A 18(1–2):45–54

    Article  CAS  PubMed  Google Scholar 

  19. Ippolito E, Natali PG, Postacchini F, Accinni L, De Martino C (1980) Morphological, immunochemical, and biochemical study of rabbit achilles tendon at various ages. J Bone Joint Surg Am 62:583–598

    Article  CAS  PubMed  Google Scholar 

  20. Jenkins EC, Ye L, Gu H, Ni SA, Velinov M, Pang D, Krinsky-McHale SJ, Zigman WB, Schupf N, Silverman WP (2010) Shorter telomeres may indicate dementia status in older individuals with Down syndrome. Neurobiol Aging 31:765–771

    Article  CAS  PubMed  Google Scholar 

  21. Jiang Y, Mishima H, Sakai S, Liu YK, Ohyabu Y, Uemura T (2008) Gene expression analysis of major lineage-defining factors in human bone marrow cells: effect of aging, gender, and age-related disorders. J Orthop Res 26:910–917

    Article  CAS  PubMed  Google Scholar 

  22. Jo CH, Lee YG, Shin WH, Kim H, Chai JW, Jeong EC, Kim JE, Shim H, Shin JS, Shin IS, Ra JC, Oh S, Yoon KS (2014) Intra-articular injection of mesenchymal stem cells for the treatment of osteoarthritis of the knee: a proof-of-concept clinical trial. Stem Cells 32:1254–1266

    Article  CAS  PubMed  Google Scholar 

  23. Kelsey JL, Hochberg MC (1988) Epidemiology of chronic musculoskeletal disorders. Ann Rev Public Health 9:379–401

    Article  CAS  Google Scholar 

  24. Koh YG, Choi YJ (2012) Infrapatellar fat pad-derived mesenchymal stem cell therapy for knee osteoarthritis. Knee 19:902–907

    Article  PubMed  Google Scholar 

  25. Kondo M, Yamaoka K, Sonomoto K, Fukuyo S, Oshita K, Okada Y, Tanaka Y (2013) IL-17 inhibits chondrogenic differentiation of human mesenchymal stem cells. PLoS ONE 8:e79463

    Article  PubMed  PubMed Central  Google Scholar 

  26. Koshy PJ, Henderson N, Logan C, Life PF, Cawston TE, Rowan AD (2002) Interleukin 17 induces cartilage collagen breakdown: novel synergistic effects in combination with proinflammatory cytokines. Ann Rheum Dis 61:704–713

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kristjánsson B, Honsawek S (2014) Current perspectives in mesenchymal stem cell therapies for osteoarthritis. Stem Cells Int 2014:194318

    Article  PubMed  PubMed Central  Google Scholar 

  28. Kyriakou C, Rabin N, Pizzey A, Nathwani A, Yong K (2008) Factors that influence short-term homing of human bone marrow-derived mesenchymal stem cells in a xenogeneic animal model. Haematologica 93:1457–1465

    Article  CAS  PubMed  Google Scholar 

  29. Li J, Pei M (2012) Cell senescence: a challenge in cartilage engineering and regeneration. Tissue Eng Part B Rev 18:270–287

    Article  CAS  PubMed  Google Scholar 

  30. Loeser RF (2011) Aging and osteoarthritis. Curr Opin Rheumatol 23:492–496

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Loeser RF (2012) The effects of aging on the development of osteoarthritis. HSS J. 8:18–19

    Article  PubMed  Google Scholar 

  32. Maerz T, Herkowitz H, Baker K (2013) Molecular and genetic advances in the regeneration of the intervertebral disc. Surg Neurol Int 4:S94–S105

    PubMed  PubMed Central  Google Scholar 

  33. Marks PH, Donaldson ML (2005) Inflammatory cytokine profiles associated with chondral damage in the anterior cruciate ligament-deficient knee. Arthroscopy 21:1342–1347

    Article  PubMed  Google Scholar 

  34. Matsukura Y, Muneta T, Tsuji K, Miyatake K, Yamada J, Abula K, Koga H, Tomita M, Sekiya I (2015) Mouse synovial mesenchymal stem cells increase in yield with knee inflammation. J Orthop Res 33:246–253

    Article  PubMed  Google Scholar 

  35. Mochizuki T, Muneta T, Sakaguchi Y, Nimura A, Yokoyama A, Koga H, Sekiya I (2006) Higher chondrogenic potential of fibrous synovium- and adipose synovium-derived cells compared with subcutaneous fat-derived cells: distinguishing properties of mesenchymal stem cells in humans. Arthritis Rheum 54:843–853

    Article  CAS  PubMed  Google Scholar 

  36. Muschler GF, Nitto H, Boehm CA, Easley KA (2001) Age- and gender-related changes in the cellularity of human bone marrow and the prevalence of osteoblastic progenitors. J Orthop Res 19:117–125

    Article  CAS  PubMed  Google Scholar 

  37. Nishimori M, Deie M, Kanaya A, Exham H, Adachi N, Ochi M (2006) Repair of chronic osteochondral defects in the rat. A bone marrow-stimulating procedure enhanced by cultured allogenic bone marrow mesenchymal stromal cells. J Bone Joint Surg Br 88:1236–1244

    Article  CAS  PubMed  Google Scholar 

  38. Nöth U, Steinert AF, Tuan RS (2008) Technology insight: adult mesenchymal stem cells for osteoarthritis therapy. Nat Clin Pract Rheumatol 4:371–380

    PubMed  Google Scholar 

  39. Orozco L, Munar A, Soler R, Alberca M, Soler F, Huguet M, Sentís J, Sánchez A, García- Sancho J (2013) Treatment of knee osteoarthritis with autologous mesenchymal stem cells: a pilot study. Transplantation 95:1535–1541

    Article  CAS  PubMed  Google Scholar 

  40. Pan J, Wang B, Li W, Zhou X, Scherr T, Yang Y, Price C, Wang L (2012) Elevated cross-talk between subchondral bone and cartilage in osteoarthritic joints. Bone 51:212–217

    Article  PubMed  Google Scholar 

  41. Peffers MJ, Thorpe CT, Collins JA, Eong R, Wei TK, Screen HR, Clegg PD (2014) Proteomic analysis reveals age-related changes in tendon matrix composition, with age- and injury-specific matrix fragmentation. J Biol Chem 289:25867–25878

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Pintan GF, de Oliveira AS, Jr LenzaM, Antonioli E, Ferretti M (2014) Update on biological therapies for knee injuries: osteoarthritis. Curr Rev Musculoskelet Med. 7:263–269

    Article  PubMed  PubMed Central  Google Scholar 

  43. Rohani L, Johnson AA, Arnold A, Stolzing A (2014) The aging signature: a hallmark of induced pluripotent stem cells? Aging Cell 13(1):2–7

    Article  CAS  PubMed  Google Scholar 

  44. Saeed H, Iqtedar M (2013) Stem cell function and maintenance—ends that matter: role of telomeres and telomerase. J Biosci 38:641–649

    Article  CAS  PubMed  Google Scholar 

  45. Saw KY, Anz A, Siew-Yoke Jee C, Merican S, Ching-Soong Ng R, Roohi SA, Ragavanaidu K (2013) Articular cartilage regeneration with autologous peripheral blood stem cells versus hyaluronic acid: a randomized controlled trial. Arthroscopy 29:684–694

    Article  PubMed  Google Scholar 

  46. Scanzello CR, Umoh E, Pessler F, Diaz-Torne C, Miles T, Dicarlo E, Potter HG, Mandl L, Marx R, Rodeo S, Goldring SR, Crow MK (2009) Local cytokine profiles in knee osteoarthritis: elevated synovial fluid interleukin-15 differentiates early from end-stage disease. Osteoarthr Cartil 17:1040–1048

    Article  CAS  PubMed  Google Scholar 

  47. Schu S, Nosov M, O’Flynn L, Shaw G, Treacy O, Barry F, Murphy M, O’Brien T, Ritter T (2012) Immunogenicity of allogeneic mesenchymal stem cells. J Cell Mol Med 16:2094–2103

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Sekiya I, Ojima M, Suzuki S, Yamaga M, Horie M, Koga H, Tsuji K, Miyaguchi K, Ogishima S, Tanaka H, Muneta T (2012) Human mesenchymal stem cells in synovial fluid increase in the knee with degenerated cartilage and osteoarthritis. J Orthop Res 30:943–949

    Article  PubMed  Google Scholar 

  49. Shane Anderson A, Loeser RF (2010) Why is osteoarthritis an age-related disease? Best Pract Res Clin Rheumatol 24:15–26

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Smith RK, Werling NJ, Dakin SG, Alam R, Goodship AE, Dudhia J (2013) Beneficial effects of autologous bone marrow-derived mesenchymal stem cells in naturally occurring tendinopathy. PLoS ONE 8:e75697

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Stenderup K, Justesen J, Clausen C, Kassem M (2003) Aging is associated with decreased maximal life span and accelerated senescence of bone marrow stromal cells. Bone 33:919–926

    Article  PubMed  Google Scholar 

  52. Stolzing A, Colley H, Scutt A (2011) Effect of age and diabetes on the response of mesenchymal progenitor cells to fibrin matrices. Int J Biomater. 2011:378034

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Stolzing A, Jones E, McGonagle D, Scutt A (2008) Age-related changes in human bone marrow-derived mesenchymal stem cells: consequences for cell therapies. Mech Ageing Dev 129:163–173

    Article  CAS  PubMed  Google Scholar 

  54. Stolzing A, Scutt A (2006) Age-related impairment of mesenchymal progenitor cell function. Aging Cell 5:213–224

    Article  CAS  PubMed  Google Scholar 

  55. Suram A, Herbig U (2014) The replicometer is broken: telomeres activate cellular senescence in response to genotoxic stresses. Aging Cell 13:780–786

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Takano T, Li YJ, Kukita A, Yamaza T, Ayukawa Y, Moriyama K, Uehara N, Nomiyama H, Koyano K, Kukita T (2014) Mesenchymal stem cells markedly suppress inflammatory bone destruction in rats with adjuvant-induced arthritis. Lab Invest 94:286–296

    Article  CAS  PubMed  Google Scholar 

  57. Teraguchi M, Yoshimura N, Hashizume H, Muraki S, Yamada H, Minamide A, Oka H, Ishimoto Y, Nagata K, Kagotani R, Takiguchi N, Akune T, Kawaguchi H, Nakamura K, Yoshida M (2014) Prevalence and distribution of intervertebral disc degeneration over the entire spine in a population-based cohort: the Wakayama Spine Study. Osteoarthr Cartil 22:104–110

    Article  CAS  PubMed  Google Scholar 

  58. Thorpe CT, Streeter I, Pinchbeck GL, Goodship AE, Clegg PD, Birch HL (2010) Aspartic acid racemization and collagen degradation markers reveal an accumulation of damage in tendon collagen that is enhanced with aging. J Biol Chem 285:15674–15681

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. van Buul GM, Siebelt M, Leijs MJ, Bos PK, Waarsing JH, Kops N, Weinans H, Verhaar JA, Bernsen MR, van Osch GJ (2014) Mesenchymal stem cells reduce pain but not degenerative changes in a mono-iodoacetate rat model of osteoarthritis. J Orthop Res 32:1167–1174

    Article  PubMed  Google Scholar 

  60. Vangsness CT Jr, Farr J 2nd, Boyd J, Dellaero DT, Mills CR, LeRoux-Williams M (2014) Adult human mesenchymal stem cells delivered via intra-articular injection to the knee following partial medial meniscectomy: a randomized, double-blind, controlled study. J Bone Joint Surg Am 96:90–98

    Article  PubMed  Google Scholar 

  61. Vega A, Martín-Ferrero MA, Del Canto F, Alberca M, García V, Munar A, Orozco L, Soler R, Fuertes JJ, Huguet M, Sánchez A, García-Sancho J (2015) Treatment of knee osteoarthritis with allogeneic bone marrow mesenchymal stem cells: a randomized controlled trial. Transplantation. doi:10.1097/TP.0000000000000678

    PubMed  Google Scholar 

  62. Wang Z, Perez-Terzic CM, Smith J, Mauck WD, Shelerud RA, Maus TP, Yang TH, Murad MH, Gou S, Terry MJ, Dauffenbach JP, Pingree MJ, Eldrige JS, Mohammed K, Benkhadra K, van Wijnen AJ, Qu W (2015) Efficacy of intervertebral disc regeneration with stem cells—a systematic review and meta-analysis of animal controlled trials. Gene 564:1–8

    Article  CAS  PubMed  Google Scholar 

  63. Wehling N, Palmer GD, Pilapil C, Liu F, Wells JW, Müller PE, Evans CH, Porter RM (2009) Interleukin-1beta and tumor necrosis factor alpha inhibit chondrogenesis by human mesenchymal stem cells through NF-kappaB-dependent pathways. Arthritis Rheum 60:801–812

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Wojdasiewicz P, Poniatowski ŁA, Szukiewicz D (2014) The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of osteoarthritis. Mediat Inflamm. doi:10.1155/2014/561459

    Google Scholar 

  65. Wong KL, Lee KB, Tai BC, Law P, Lee EH, Hui JH (2013) Injectable cultured bone marrow-derived mesenchymal stem cells in varus knees with cartilage defects undergoing high tibial osteotomy: a prospective, randomized controlled clinical trial with 2 years’ follow-up. Arthroscopy 29:2020–2028

    Article  PubMed  Google Scholar 

  66. Yang YM, Li P, Cui DC, Dang RJ, Zhang L, Wen N, Jiang XX (2015) Effect of aged bone marrow microenvironment on mesenchymal stem cell migration. Age (Dordr) 37:16

    Article  Google Scholar 

  67. Yelin EH, Trupin LS, Sebesta DS (1999) Transitions in employment, morbidity, and disability among persons ages 51–61 with musculoskeletal and non-musculoskeletal conditions in the US, 1992–94. Arthritis Rheumatol 42:769–779

    Article  CAS  Google Scholar 

  68. Zhang J, Wang JH (2014) PRP treatment effects on degenerative tendinopathy—an in vitro model study. Muscles Ligaments Tendons J 4:10–17

    PubMed  PubMed Central  Google Scholar 

  69. Zhou Z, Akinbiyi T, Xu L, Ramcharan M, Leong DJ, Ros SJ, Colvin AC, Schaffler MB, Majeska RJ, Flatow EL, Sun HB (2010) Tendon-derived stem/progenitor cell aging: defective self-renewal and altered fate. Aging Cell 9:911–915

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Zhu X, Yuan F, Li H, Zheng Y, Xiao Y, Yan F (2013) Evaluation of canine bone marrow-derived mesenchymal stem cells after long-term cryopreservation. Zool Sci 30:1032–1037

    Article  PubMed  Google Scholar 

  71. Zimmermann S, Voss M, Kaiser S, Kapp U, Waller CF, Martens UM (2003) Lack of telomerase activity in human mesenchymal stem cells. Leukemia 17:1146–1149

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Kivanc Atesok.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Atesok, K., Fu, F.H., Sekiya, I. et al. Stem cells in degenerative orthopaedic pathologies: effects of aging on therapeutic potential. Knee Surg Sports Traumatol Arthrosc 25, 626–636 (2017). https://doi.org/10.1007/s00167-015-3763-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00167-015-3763-9

Keywords

Navigation