Evidence that Osteoblasts are Specialized Citrate-producing Cells that Provide the Citrate for Incorporation into the Structure of Bone

摘要

Citrate is a major component of bone in all vertebrates, but its implications in bone have remained largelyunknown. Recent studies identified that citrate is incorporated into the structure of the hydroxyapatitenanocrystal/collagen complex; and is essential for the important biomechanical properties of bone. This raises theimportant question, “What is the source of citrate for incorporation into bone?”; A question that heretofore had remainedunresolved. Studies in this report were designed to determine the plausibility of our concept that the osteoblasts arespecialized citrate-producing cells, which provide the citrate that is incorporated into the structure of bone; and thatosteogenic differentiation of mesenchyme cells leads to the development of the citrate-producing osteoblasts. The resultsdemonstrated that primary human osteoblasts exhibit the capability of citrate-production. Undifferentiated mesenchymecells do not exhibit the capability of citrate production; and osteogenic differentiation results in citrate-producingosteoblasts. The up-regulation of zinc uptake transporter ZIP1 is essential for the manifestation of the citrate-producingcapability of the osteoblasts. We determined that osteoblast transport of citrate from plasma is not a likely source of citratein bone. Thus, this study establishes for the first time that the osteoblasts are specialized citrate-producing cells thatprovide the citrate for incorporation into the structure of bone; and that mesenchyme cell osteogenesis leads todifferentiated citrate-producing osteoblasts. This is a new understanding; which must include the osteogenic developmentof citrate-producing osteoblasts, and the process of “citration” in concert with mineralization during bone formation. Italso provides a new understanding of the role of bone in the homeostatic maintenance of plasma citrate concentration.