Abstract
The purpose of our study was to evaluate the role of macrophage migration inhibitory factor (MIF) in the differentiation of tendon-derived stem cells (TdSCs) under hyperglycemic conditions. In the in vivo experiment, rats were classified into diabetic (DM) and non-DM groups depending on the intraperitoneal streptozotocin (STZ) or saline injection. Twelve-week after STZ injection, the supraspinatus tendon was harvested and prepared for histological evaluation and real-time reverse transcription polymerase chain reaction for osteochondrogenic (aggrecan, BMP-2, and Sox9) and tenogenic (Egr1, Mkx, scleraxis, type 1 collagen, and Tnmd) markers. For the in vitro experiment, TdSCs were isolated from healthy rat Achilles tendons. Cultured TdSCs were treated with methylglyoxal and recombinant MIF or MIF gene knockdown to determine the effect of hyperglycemic conditions and MIF on the differentiation function of TdSCs. These conditions were classified into four groups: hyperglycemic-control group, hyperglycemic-recombinant-MIF group, hyperglycemic-knockdown-MIF group, and normal-control group. The mRNA expression of osteochondrogenic and tenogenic markers was compared among the groups. In the in vivo experiment, the mRNA expression of all osteochondrogenic and tenogenic differentiation markers in the DM group was significantly higher and lower than that in the non-DM group, respectively. Similarly, in the in vitro experiments, the expression of all osteochondrogenic and tenogenic differentiation markers was significantly upregulated and downregulated, respectively, in the hyperglycemic-control group compared to that in the normal-control group. The hyperglycemic-knockdown-MIF group demonstrated significantly decreased expression of all osteochondrogenic differentiation markers and increased expression of only some tenogenic differentiation markers compared with the hyperglycemic-control group. In contrast, the hyperglycemic-recombinant-MIF group showed significantly increased expression of all osteochondrogenic differentiation markers, but no significant difference in any tenogenic marker level, compared to the hyperglycemic-control group. These results suggest that tendon homeostasis could be affected by hyperglycemic conditions, and MIF appears to alter the differentiation of TdSCs via enhancement of the osteochondrogenic differentiation in hyperglycemic conditions. These are preliminary findings, and must be confirmed in a further study.
Highlights
Tendinopathy is a common musculoskeletal pathology that causes pain and dysfunction and commonly occurs around the shoulder, elbow, and ankle joints [1]
Previous studies reported that tendon-derived stem cells (TdSCs) in diabetic conditions tended to erroneously differentiate toward osteochondrogenesis rather than tenogenesis, which explains the pathogenesis of tendon disorders in diabetes [11,23,24]
Under hyperglycemic condition, the expression of all osteochondrogenic differentiation markers significantly changed depending on the administration of recombinant migration inhibitory factor (MIF) (Figure 4A), while none of the tenogenic markers was affected by the administration of recombinant MIF (Figure 4B). These findings suggest that MIF is more likely to augment osteochondrogenic differentiation rather than inhibit tenogenic differentiation under hyperglycemic conditions
Summary
Tendinopathy is a common musculoskeletal pathology that causes pain and dysfunction and commonly occurs around the shoulder, elbow, and ankle joints [1]. Tendinopathy refers to a pathological condition in which disrupted tendon healing (degeneration) overwhelms the normal healing process (repair) in the tendon after acute or repetitive cumulative injury [2]. The normal tendon healing process involves three sequential and overlapping phases: inflammation, proliferation, and remodeling [3,4]. Overwhelming of the healing process as with disrupted tendons can progress to chronic mucoid and/or lipoid degeneration of the tendon with a variable amount of fibrocartilaginous metaplasia and calcium hydroxyapatite deposits [5,6,7]. Tendinopathy in diabetes is a complex, multifactorial, pathological process involving altered macrophage function, angiogenic signaling, and neurotrophic signaling under both a chronic, low-grade inflammation and a high-glucose environment [13,14,15,16]
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