Geriatric fragility fractures are associated with a human skeletal stem cell defect

Abstract

Fragility fractures have a limited capacity to regenerate, and impaired fracture healing is a leading cause of morbidity in the elderly. The recent identification of a highly purified bona fide human skeletal stem cell (hSSC) and its committed downstream progenitor cell populations provides an opportunity for understanding the mechanism of age‐related compromised fracture healing from the stem cell perspective. In this study, we tested whether hSSCs isolated from geriatric fractures demonstrate intrinsic functional defects that drive impaired healing. Using flow cytometry, we analyzed and isolated hSSCs from callus tissue of five different skeletal sites ( n = 61) of patients ranging from 13 to 94 years of age for functional and molecular studies. We observed that fracture‐activated amplification of hSSC populations was comparable at all ages. However, functional analysis of isolated stem cells revealed that advanced age significantly correlated with reduced osteochondrogenic potential but was not associated with decreased in vitro clonogenicity. hSSCs derived from women displayed an exacerbated functional decline with age relative to those of aged men. Transcriptomic comparisons revealed downregulation of skeletogenic pathways such as WNT and upregulation of senescence‐related pathways in young versus older hSSCs. Strikingly, loss of Sirtuin1 expression played a major role in hSSC dysfunction but re‐activation by trans‐resveratrol or a small molecule compound restored in vitro differentiation potential. These are the first findings that characterize age‐related defects in purified hSSCs from geriatric fractures. Our results provide a foundation for future investigations into the mechanism and reversibility of skeletal stem cell aging in humans.

A Review of Recent Developments in the Molecular Mechanisms of Bone Healing

“…The loss of sirtuin1 expression played an important role in hSSC dysfunction, although reactivation by trans-resveratrol or a small molecular compound restored the differentiation potential in vitro. These findings demonstrate the age-related defects in purified hSSCs in geriatric fractures and could serve as a basis for further research into the functional mechanism and reversibility of skeletal stem cell aging in humans [ 79 ].…”

Delayed Union of a Diaphyseal Forearm Fracture Associated With Impaired Osteogenic Differentiation of Prospectively Isolated Human Skeletal Stem Cells

“…We recently reported on a clinical series of 61 patients that prospective SSC isolation from fracture sites showed comparable functional readouts in patients of similar age, even across multiple skeletal sites. ( 20 ) In this case, the index patient was treated with bridge plating and intended secondary bone healing, whereas the comparison was treated with compression plating. Thus, slightly different surgical techniques were used, although both were viable fixation strategies.…”

“…It is possible that clonogenicity decreases in activated SSCs at injury sites that become poised to differentiate along the osteochondrogenic lineage, explaining the decreased CFUs‐F in patient B. Additionally, we have observed SSC abundance does not correlate with CFU‐F percentage, and that functional differentiation capacity correlates more closely with differences in fracture healing than quantitative differences in other subpopulations. ( 20 ) In this study, the assays performed were limited to in vitro assessments of clonogenicity and skeletal differentiation. However, the in vivo stem cell properties of hSSCs have previously been validated.…”

“…1A) using fluorescence-activated cell sorting (FACS) that is capable of multilineage skeletal differentiation, (18) allowing us to perform detailed molecular and functional investigations into skeletal development, growth, and regeneration. (19,20) In this case report, we describe a situation in which prospectively isolated hSSCs, collected at the time of fracture fixation, predicted compromised fracture healing, despite the fact that the patient was young and healthy, in a fracture at generally low risk for compromised healing and with technically appropriate surgery.…”

Targeting Senescent Cells for a Healthier Aging: Challenges and Opportunities

“…Sirtuins [ 156] Piperlongumine Natural (piper plants) Caspase 3 [58] FOXO4-DRI peptide Synthetic FOXO4-p53 interaction [48] Alvespimycin (17-DMAG) Synthetic (geldanamycin derivative) HSP90 [47] Senomorphics Apigenin Natural (plants, fruits, vegetables, tea) NF-B [94] Kaempferol Natural (fruits, vegetables) NF-B [94] Glucosamine Natural (Dietary supplements) ROS, p21 CIP1 , autophagy [ 157,158] Nordihydroguaiaretic acid (NDGA) Natural (Creosote bush) p300 acetyltransferase [97] Resveratrol Natural (fruits, red wine, dietary supplements) SIRT1 [ 159,160] Rapamycin S. hygroscopicus mTOR [ 103,104] Metformin Synthetic AMPK [ 161,162] Ruxolitinib Synthetic JAK1/2 [ 163] SB203580 Synthetic p38MARPK [ 101] 5Z-7-oxozeaenol Synthetic TAK1 [ 106] or more accurately, personalized. In response to the urgent and unmet clinical, healthcare, workforce, and economic needs of global aging populations who are suffering from aging-related conditions and multimorbidity, the world health organization (WHO) has recently called for a public health attention based on the law of human rights.…”