Osteocytes but not osteoblasts directly build mineralized bone structures.

Abstract

Bone-forming osteoblasts have been a cornerstone of bone biology for more than a century. Most research toward bone biology and bone diseases center on osteoblasts. Overlooked are the 90% of bone cells, called osteocytes. This study aims to test the hypothesis that osteocytes but not osteoblasts directly build mineralized bone structures, and that defects in osteocytes lead to the onset of hypophosphatemia rickets. The hypothesis was tested by developing and modifying multiple imaging techniques, including both in vivo and in vitro models plus two types of hypophosphatemia rickets models (Dmp1-null and Hyp, Phex mutation mice), and Dmp1-Cre induced high level of β-catenin models. Our key findings were that osteocytes (not osteoblasts) build bone similar to the construction of a high-rise building, with a wire mesh frame (i.e., osteocyte dendrites) and cement (mineral matrices secreted from osteocytes), which is a lengthy and slow process whose mineralization direction is from the inside toward the outside. When osteoblasts fail to differentiate into osteocytes but remain highly active in Dmp-1-null or Hyp mice, aberrant and poor bone mineralization occurs, caused by a sharp increase in Wnt-β-catenin signaling. Further, the constitutive expression of β-catenin in osteocytes recaptures a similar osteomalacia phenotype as shown in Dmp1 null or Hyp mice. Thus, we conclude that osteocytes directly build bone, and osteoblasts with a short life span serve as a precursor to osteocytes, which challenges the existing dogma.

• Authors: Ke Wang, Yinshi Ren, Shuxian Lin, Yan Jing, Chi Ma, Jun Wang, X Baozhi Yuan, Xianglong Han, Hu Zhao, Zheng Wang, Minghao Zheng, Yin Xiao, Lin Chen, Bjorn Reino Olsen, Jian Q Feng
• Journal: International journal of biological sciences (Int J Biol Sci) Vol. 17 Issue 10 Pg. 2430-2448 ( 2021) ISSN: 1449-2288 [Electronic] Australia
• PMID: 34326685 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: © The author(s).

Chemical References

• Dmp1 protein, mouse
• Extracellular Matrix Proteins
• beta Catenin
• PHEX Phosphate Regulating Neutral Endopeptidase
• Phex protein, mouse

Topics

• Age Factors
• Animals
• Bone Density
• Bone and Bones (metabolism)
• Calcification, Physiologic (physiology)
• Disease Models, Animal
• Extracellular Matrix Proteins (genetics)
• Familial Hypophosphatemic Rickets (blood, metabolism, pathology)
• Femur (transplantation)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Osteoblasts (metabolism)
• Osteocytes (metabolism, ultrastructure)
• PHEX Phosphate Regulating Neutral Endopeptidase (genetics)
• Tibia (transplantation)
• Wnt Signaling Pathway
• beta Catenin (metabolism)