Abstract
Chronic metabolic acidosis leads to bone-remodelling disorders based on excessive mineral matrix resorption and inhibition of bone formation, but also affects the homeostasis of citrate, which is an essential player in maintaining the acid–base balance and in driving the mineralisation process. This study aimed to investigate the impact of acidosis on the osteogenic properties of bone-forming cells and the effects of citrate supplementation in restoring the osteogenic features impaired by the acidic milieu. For this purpose, human mesenchymal stromal cells were cultured in an osteogenic medium and the extracellular matrix mineralisation was analysed at the micro- and nano-level, both in neutral and acidic conditions and after treatment with calcium citrate and potassium citrate. The acidic milieu significantly decreased the citrate release and hindered the organisation of the extracellular matrix, but the citrate supplementation increased collagen production and, particularly calcium citrate, promoted the mineralisation process. Moreover, the positive effect of citrate supplementation was observed also in the physiological microenvironment. This in vitro study proves that the mineral matrix organisation is influenced by citrate availability in the microenvironment surrounding bone-forming cells, thus providing a biological basis for using citrate-based supplements in the management of bone-remodelling disorders related to chronic low-grade acidosis.
Highlights
In the past twenty years, a growing body of research has unequivocally demonstrated the strong, causal relationship between acidosis and the pathophysiology of bone disease [1,2,3,4,5,6]
A slowing down in the mineralisation process was testified to by the significant decrease in calcium deposition assessed by elution and spectrophotometry measurement of the Alizarin Red S (Figure 2e)
Fourier Transform Infrared Spectroscopy (FT-IR) spectroscopy has been proposed as a powerful technique for the characterisation of proteins and collagen-based materials, and we focused on Amide I and Amide II which are considered to be the two main markers of collagen structure [45,46,47,48,49]
Summary
In the past twenty years, a growing body of research has unequivocally demonstrated the strong, causal relationship between acidosis and the pathophysiology of bone disease [1,2,3,4,5,6]. Severe acidosis with acidemia occurs when compensatory measures for maintaining the acid–base equilibrium fail and the blood pH value drops below 7.35, while chronic low-grade acidosis is the result of the continual adaptation of the body to a variety of physiological and pathological conditions, including ageing, Nutrients 2020, 12, 3779; doi:10.3390/nu12123779 www.mdpi.com/journal/nutrients. The prompt skeletal response to acute metabolic acidosis is a physicochemical reaction aimed at buffering hydrogen ions by means of alkali metals (sodium, potassium), carbonate and phosphate groups, resulting in a net calcium efflux from the mineralised matrix [1,2]. The resorption activity of osteoclasts increases dramatically when the intra-bone pH drops below 6.9 and, acidosis significantly inhibits the osteogenic function of osteoblasts, including the production of extracellular matrix, the activity of alkaline phosphatase and the formation of trabecular bone [4,8]
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