Abstract
The accumulation of senescent cells is implicated in the pathology of several age-related diseases. While the clearance of senescent cells has been suggested as a therapeutic target for patients with osteoarthritis (OA), cellular senescence of bone-resident osteoblasts (OB) remains poorly explored. Since oxidative stress is a well-known inducer of cellular senescence, we here investigated the effect of antioxidant supplementation on the isolation efficiency, expansion, differentiation potential, and transcriptomic profile of OB from osteoarthritic subchondral bone. Bone chips were harvested from sclerotic and non-sclerotic regions of the subchondral bone of human OA joints. The application of 0.1 mM ascorbic acid-2-phosphate (AA) significantly increased the number of outgrowing cells and their proliferation capacity. This enhanced proliferative capacity showed a negative correlation with the amount of senescent cells and was accompanied by decreased expression of reactive oxygen species (ROS) in cultured OB. Expanded cells continued to express differentiated OB markers independently of AA supplementation and demonstrated no changes in their capacity to osteogenically differentiate. Transcriptomic analyses revealed that apoptotic, cell cycle–proliferation, and catabolic pathways were the main pathways affected in the presence of AA during OB expansion. Supplementation with AA can thus help to expand subchondral bone OB in vitro while maintaining their special cellular characteristics. The clearance of such senescent OB could be envisioned as a potential therapeutic target for the treatment of OA.
Highlights
Osteoarthritis (OA) is the most prevalent degenerative joint disorder and a main reason for chronic pain and disability in the elderly population [1]
In vitro studies have demonstrated that osteoblasts (OB) from patients with OA significantly influenced the metabolic activity of human chondrocytes [12,13], e.g., by upregulating the expression of extracellular matrix degrading enzymes, such as matrix metalloproteinase-3 (MMP-3) and matrix metalloproteinase-13 (MMP-13) [14,15]
SOci.B201(7p, 1e8r, 2g51r7am of tissue) was observed to grow out from bone chips3ionf 1t8he presence of AA (2.5 ± 1.21. -Rfeosludltsincrease, p = 0.0072 for Sc_OB, and 2.1 ± 0.6-fold increase; p = 0.0135 for N_OB) as compared to the number of OB growing out from the corresponding bone chips cultured in standard culture mediu2m.1. (ECffeMct o)f(AFsicgorubirceAc1idAo)n. tCheoOnuvtgerorwsethlyan, dstParotliisfetriactiaonllyRasteigofnHiufimcaannOtsdteoiafrftehrreitinc cOeBs were not detected between the twhaorvOeFsiBtresdtt,ywfproeemsasrsseecgslesareodrtdictihn(eSgcin_tOfhluBee)nmacneedaofnnAonnAu-scmolnebrotehtirec oo(uNf to_gOuroBtwg) trohostweefofiiacnrietghnrcciyteiclolfssuhebuictmhhoaennrdpraartlimcboaornnyet.rOoABl conditions (CM) or in thespigrneifsiceanntcley ioncfr0ea.1sedmnMumAbeAr of(FOiBg(uperreg1raAm)o. f tissue) was observed to grow out from bone chips
Summary
Osteoarthritis (OA) is the most prevalent degenerative joint disorder and a main reason for chronic pain and disability in the elderly population [1]. The temporal sequence of bone and cartilage changes might vary according to the disease phenotype or the animal model, it is commonly agreed that the interplay between these tissues is crucially involved in the development of OA [10,11] In this regard, in vitro studies have demonstrated that osteoblasts (OB) from patients with OA significantly influenced the metabolic activity of human chondrocytes [12,13], e.g., by upregulating the expression of extracellular matrix degrading enzymes, such as matrix metalloproteinase-3 (MMP-3) and matrix metalloproteinase-13 (MMP-13) [14,15]. This can be most possibly due to the altered characteristics of OB from osteoarthritic tissues, e.g., in terms of their abnormal production of extracellular matrix components [16] or of other factors, such as cartilage degrading mediators and growth factors, as compared to OB from healthy subchondral bone [17,18,19]
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