Theobromine Upregulates Osteogenesis by Human Mesenchymal Stem Cells In Vitro and Accelerates Bone Development in Rats

Abstract

Theobromine (THB) is one of the major xanthine-like alkaloids found in cacao plant and a variety of other foodstuffs such as tea leaves, guarana, and cola nuts. Historically, THB and its derivatives have been utilized to treat cardiac and circulatory disorders, drug-induced nephrotoxicity, proteinuria and as an immune-modulator. Our previous work demonstrated that THB has the capacity to improve the formation of hydroxyl-apatite during tooth development, suggesting that it may also enhance skeletal development. With its excellent safety profile and resistance to pharmacokinetic elimination, we reasoned that it might be an excellent natural osteoanabolic supplement during pregnancy, lactation and early postnatal growth. To determine whether THB had an effect on human osteoprogenitors, we subjected primary human bone marrow mesenchymal stem cells (hMSCs) to osteogenic assays after exposure to THB in vitro and observed that THB exposure increased the rate of osteogenesis and mineralization by hMSCs. Moreover, THB exposure resulted in a list of up-regulated mRNA transcripts that best matched an osteogenic tissue expression signature as compared to other tissue expression signatures archived in several databases. To determine whether oral administration of THB resulted in improved skeletal growth, we provided pregnant rats with chow supplemented with THB during pregnancy and lactation. After weaning, offspring received THB continuously until postnatal day 50 (approximately 10 mg kg−1 day−1). Administration of THB resulted in neonates with larger bones and 50 day old offspring accumulated greater body mass, longer and thicker femora and superior tibial trabecular parameters. The accelerated growth did not adversely affect the strength and resilience of the bones. These results indicate that THB increases the osteogenic potential of bone marrow osteoprogenitors, and dietary supplementation of a safe dose of THB to expectant mothers and during the postnatal period could accelerate skeletal development in their offspring.

Effect of maternal and postnatal cocoa supplementation on testicles of adult Wistar rats

“…The supplementation with theobromine (the compound present in Theobroma cacao) has beneficial effects on the bone health of rats (longer and thicker femurs and better tibial trabecular parameters). 31,32 However, our study showed no significant difference in the bone mineral content and the bone area of animals supplemented with cocoa powder, suggesting the need for further studies to clarify the effects of cocoa administration on bone parameters.…”

Stimulatory Effects of KPR-A148 on Osteoblast Differentiation and Bone Regeneration

“…2). A previous report showed that theobromine, a natural xanthine derivative, stimulated bone formation at a high concentration [19]. Although both xanthine derivatives have similar effects on osteoblasts, KPR-A148 is structurally distinct from theobromine, indicating that KPR-A148 is a new xanthine derivative capable of inducing osteoblast differentiation.…”

“…Theobromine exposure on human mesenchymal stem cells promoted osteogenesis and the rate of mineralization. Also, oral administration of theobromine via dietary food from pregnancy until postnatal days accelerated the bone development in rats [19]. Pentoxifylline [3,7-dimethyl-1-(5-oxohexyl) purine-2,6-dione], a synthetic xanthine derivative, has also been reported to have a positive effect on bone homeostasis.…”

Conditioned Medium of Mesenchymal Stem Cells Pulsed with Theobromine Can Instruct Anti-Inflammatory Neutrophils

“…The in vitro results showed that theobromine upregulated osteogenesis and simultaneously downregulated adipogenesis by MSCs (36). Therefore, changes in other functions of stem cells by theobromine, such as their interaction with immune cells, are plausible.…”