The Important Role of Osteoblasts and Citrate Production in Bone Formation: “Osteoblast Citration” as a New Concept for an Old Relationship

Abstract

It has been known for about seventy years that bone, in all vertebrates, contains uniquely high citrate levels. However, the role of citrate, its source, its regulation, and its implication in normal bone formation and in bone disorders have remained largely unknown. For the past thirty-five years, the relationship of citrate in bone has been a neglected area of attention and research. It has recently been discovered that citrate is critical for the structure of the apatite nanocrystal, and is required to impart the important properties of bone such as its stability, strength, and resistance to fracture. This brings to focus the need for a renewed interest and research into the relationships of citrate in bone formation. A most fundamental question that must be resolved is “What is the source of citrate in bone?”. This presentation provides a historical review of the early research to the present status of citrate implications in bone. This leads to a new concept of the role of osteoblasts as specialized citrate producing cells that provide the source of citrate in bone formation; i.e. the “osteoblast citration” process. This also brings into focus a new insight into the role of zinc in bone in relation to osteoblast citrate production. The genetic/hormonal/metabolic relationships of “net citrate production” are described. The intent of this presentation is to provide the background for a new perspective of the important implications of osteoblasts and citrate in bone formation; which, hopefully, will stimulate a renewed interest and essential research.

Citrate-Based Biomaterials and Their Applications in Regenerative Engineering

“…Although its function in bone formation remains largely unknown, recent research has discovered that citrate plays a large role in bone's unique stability, strength, and resistance to fracture by regulating apatite nanocrystal growth (84–86). These recent findings have created a renewed interest in the role of citrate in bone physiology and development and provided a new hypothesis that osteoblasts are specialized citrate-producing cells that provide the necessary levels of citrate for proper bone formation (85, 87). A recent study has shown that citrate, whether presented on a biomaterial surface or supplemented into cell culture media, has unique effects on gene expression: It upregulates osterix, alkaline phosphatase, and osteopontin and downregulates osteocalcin in C2C12 myoblasts and human mesenchymal stem cells (88).…”

Development of injectable citrate-based bioadhesive bone implants

“…28 Costello et al discussed the speculated roles of citrate metabolism and production for the osteogenic differentiation of stem cells and bone formation. 29, 30 These latest findings are strong evidence that citrate should be involved in bone substitute design and has led to the development of a series of citrate-based composites for bone applications including poly (diol citrates)-HA (POC-HA), poly (ethylene glycol) maleate citrate-HA (PEGMC-HA), and citrate-based polymer blends-HA (CBPB-HA). 31–36 …”

Aerobic Glycolysis in Osteoblasts

“…It is possible that aerobic glycolysis is necessary to fulfill the specific metabolic needs of osteoblasts. For instance, osteoblasts have been long known to produce and secrete a large amount of citrate 25,26 . Citrate in bone was recently shown to be critical for the structure of the apatite nanocrystal, providing stability, strength, and resistance to fracture 27–29 .…”