Norepinephrine Inhibition of Mesenchymal Stem Cell and Chondrogenic Progenitor Cell Chondrogenesis and Acceleration of Chondrogenic Hypertrophy

Abstract

Objective. Mesenchymal progenitor cell chondrogenesis is the biologic platform for the generation or regeneration of cartilage, but the external influence of the sympathetic nervous system on this process is not yet known. Sympathetic nerve fibers are present in articular tissue, and the sympathetic nervous system influences the musculoskeletal system by, for example, increasing osteoclastogenesis. This study was initiated to explore the role of the sympathetic neurotransmitter norepinephrine (NE) in mesenchymal stem cell (MSC)-dependent and cartilage progenitor cell (CPC)-dependent chondrogenesis.Methods. Using human MSCs or CPCs, chondrogenic differentiation was induced in the presence of NE, the specific ␤-adrenergic receptor (␤-AR) agonist isoproterenol, and the specific ␤-AR antagonist nadolol. We studied sympathetic nerve fibers, tyrosine hydroxylase (TH) expression, catecholamine biosynthesis, and synovial fluid levels in human joints, as well as cartilage-specific matrix deposition during differentiation.Results. TH؉ sympathetic nerve fibers were present in the synovial tissue, meniscus, and subchondral bone marrow. In addition, synovial fluid from patients with knee trauma demonstrated high concentrations of NE. During MSC or CPC chondrogenesis, ␤-AR were expressed. Chondrogenic aggregates treated with NE or isoproterenol synthesized lower amounts of type II collagen and glycosaminoglycans. NE and isoproterenol treatment dose-dependently increased the levels of cartilage hypertrophy markers (type X collagen and matrix metalloproteinase 13). Nadolol reversed the inhibition of chondrogenesis and the up-regulation of cartilage hypertrophy.Conclusion. Our findings demonstrate NEdependent inhibition of chondrogenesis and acceleration of hypertrophic differentiation. By inhibiting cartilage repair, these sympathetic influences can be important after joint trauma. These findings may be a basis for novel neurochondrogenic therapeutic options.

Absence of substance P and the sympathetic nervous system impact on bone structure and chondrocyte differentiation in an adult model of endochondral ossification

“…Fracture callus of sympathectomized mice consists of a higher proportion of mesenchymal callus tissue and a lower proportion of cartilaginous callus tissue early after fracture suggesting that the absence of sympathetic neurotransmitters delays differentiation of mesenchymal callus tissue toward a cartilaginous matrix. This observation corresponds to in vitro data which demonstrate that norepinephrine (NE) stimulation of mesenchymal stem cells (MSC), kept in micromass pellets, dose-dependently inhibits chondrogenic differentiation via ß-adrenoceptors as chondrogenic MSC aggregates treated with NE or isoproterenol (ß-adrenoceceptor agonist) synthesized lower amounts of type II collagen and glycosaminoglycans (Jenei-Lanzl et al, 2014). Notably, the absence of both SP and the SNS reduce callus area positive for hypertrophic chondrocytes in the late phase of callus remodeling where matrix mineralization starts and the hard callus is formed.…”

“…Notably, the absence of both SP and the SNS reduce callus area positive for hypertrophic chondrocytes in the late phase of callus remodeling where matrix mineralization starts and the hard callus is formed. This effect is according to in vitro data which demonstrate that NE accelerates hypertrophic differentiation by inducing hypertrophic markers collagen X and MMP-13 in chondrogenically differentiated MSC (Jenei-Lanzl et al, 2014). We demonstrated previously, that stimulation of murine costal chondrocytes kept in micromass pellets with SP temporarily induces mmp-13 gene expression whereas col10a1 gene expression was unaffected (Opolka et al, 2012).…”

The brain–joint axis in osteoarthritis: nerves, circadian clocks and beyond

“…However, in vitro and ex vivo studies show that ANS-related neurotransmitters can influence chondrogenesis [42][43][44][45] . A few studies have looked at the role of adrenergic receptors present at the surface of chondrocytes, including in human OA cartilage Indeed, β 2 adrenergic receptors and α 2 adrenergic receptors are both expressed on epiphyseal proliferating chondrocytes [44][45][46][47][48][49] .…”

“…ANS, autonomic nervous system; CNS, central nervous system; HPA axis, hypothalamic-pituitary-adrenal axis; HPT axis, hypothalamic-pituitary-thyroid axis; OA, osteoarthritis. 43 have demonstrated that noradrenaline can inhibit chondrogenesis and accelerate hypertrophic differentiation. Collectively, these studies tentatively point towards a role of the ANS in the regulation of OA-related pathways, although unequivocal evidence is still lacking.…”

β-Blockade use for Traumatic Injuries and Immunomodulation

“…(61, 62) Mesenchymal stem cells (MSCs) express β adrenergic receptors and are critical for maintaining hematopoietic stem cell pluripotency and facilitating orderly differentiation. (63, 64) Although NE has been shown to inhibit MSC chondrogenesis, (65) the effects of β-blockers on MSC modulation of erythropoiesis have not yet been reported. In addition, post-injury inflammation has been shown to increase hepcidin, thereby decreasing intestinal iron absorption and reducing the amount of substrate available for erythropoiesis.…”