Essential role of the metabolite α-ketoglutarate in bone tissue and bone-related diseases

Abstract

Bone metabolism in bone tissue is constantly maintained in a state of dynamic equilibrium. The mass of bone and joint tissues is determined by both bone formation and bone resorption. It is hypothesized that disrupted metabolic balance leads to osteoporosis, osteoarthritis, rheumatoid arthritis, and bone tumors. Such disruptions often manifest as either a reduction or abnormality in bone mass and are frequently accompanied by pathological changes such as inflammation, fractures, and pain. α-Ketoglutarate (α-KG) serves as a pivotal intermediate in various metabolic pathways in mammals, significantly contributing to cellular energy metabolism, amino acid metabolism, and other physiological processes. α-KG may be a therapeutic target for a variety of bone-related diseases, such as osteoporosis, osteoarthritis, and rheumatoid arthritis, because of its role in maintaining the metabolic balance of bone. After the application of α-KG, bone loss and inflammation in bone tissue are alleviated. This review focuses on the regulatory effects of α-KG on various cells in bone and joint tissues. Owing to the regulatory effect of α-KG on the balance of bone metabolism, the application of α-KG in the treatment of osteoporosis, osteoarthritis, rheumatoid arthritis, bone tumors, and other bone tissue diseases has been clarified.

1. Introduction

As an intermediate in a variety of metabolic processes, α-ketoglutarate (α-KG) is also known as 2-oxoglutarate and is closely involved in the energy metabolism process represented by carbohydrate metabolism in the body [1]. Carbohydrate metabolism depends on the energy supply of the tricarboxylic acid cycle (TCA), which is the main pathway for acetyl-CoA to completely decompose into water and carbon dioxide and generate energy, and it is also the precursor source of much biosynthesis [2]. α-KG, as a rate-determining intermediate, is crucial in cell energy metabolism because it connects intracellular carbon and nitrogen metabolism between isocitrate and succinyl coenzyme A. Additionally, α-KG is closely involved in the amino acid cycle [3]. As a precursor of amino acids such as glutamine and glutamic acid, α-KG plays a direct role in energy production and a wide range of cellular chemical reactions. α-KG provides an energy source, stimulating protein synthesis, inhibiting protein degradation in muscle, and serving as a significant metabolic fuel for gastrointestinal cells [2]. In the intestine, proline, leucine, and other amino acids are formed by α-KG in the intestinal epithelium [4]. Moreover, studies have shown that the synthesis of ketoglutarate reductive amination around blood vessels is also an important source of glutamic acid in bone tissue [5].

The dynamic balance between mature osteoblast activity and osteoclast activity involves complex processes affecting bone metabolism [6,7]. Various bone-related diseases are often accompanied by a loss of balance between osteoblast and osteoclast activity, as well as inflammatory lesions in cartilage and synovial tissue. Furthermore, the proliferation, differentiation and apoptosis of various cells in bone tissue are closely related to energy metabolism [8]. The activation of mitochondrial physiological activities and the metabolic transition to oxidative phosphorylation are involved in the differentiation, proliferation, and maturation of mesenchymal stem cells (MSCs) [9]. In one recent study, the levels of mitochondrial biogenesis-related proteins were found to be elevated, along with increased levels of tricarboxylate cyclase and respiratory chain complex subunits. This resulted in an increase in oxygen consumption, the mitochondrial membrane potential, and the intracellular ATP content, indicating that the oxidative metabolism of mitochondria is enhanced during bone metabolism [10]. The effect of α-KG on bone tissue is affected by a variety of mechanisms. The production and utilization of α-KG not only changes the bone metabolism balance but also affects bone mass. α-KG also affects the proliferation and differentiation of various cells in bone tissue by promoting osteogenesis, inhibiting osteoclast differentiation, and enhancing the proliferation of chondrocytes.