Int J Biol Sci 2021; 17(10):2430-2448. doi:10.7150/ijbs.61012

Research Paper

Osteocytes but not osteoblasts directly build mineralized bone structures

Ke Wang1#, Yinshi Ren1,2#, Shuxian Lin1,3, Yan Jing4, Chi Ma1,2, Jun Wang1,5, X. Baozhi Yuan6, Xianglong Han1,5, Hu Zhao7, Zheng Wang1, Minghao Zheng8, Yin Xiao9, Lin Chen10, Bjorn Reino Olsen11, Jian Q. Feng1✉

1. Department of Biomedical Sciences, Texas A&M University College of Dentistry, Dallas, TX 75246, USA.
2. Center for Excellence in Hip Disorders, Texas Scottish Rite Hospital for Children, Dallas, TX 75219 USA.
3. Laboratory of Oral Biomedical Science and Translational Medicine, School of Stomatology, Tongji University, Shanghai, 200092, China.
4. Department of Orthodontics, Texas A&M University College of Dentistry, Dallas, TX 75246, USA.
5. State Key Laboratory of Oral Diseases, National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu, 610041, China.
6. Angitia Biopharmaceuticals, Guangzhou, 510000, China.
7. Department of Restorative Dentistry, Texas A&M University College of Dentistry, Dallas, TX 75246, USA.
8. Centre for Orthopaedic Research, School of Surgery, The University of Western Australia, Perth, 6009, Australia.
9. Institute of Health and Biomedical Innovation, Queensland University of Technology, Brisbane, Queensland, 4059, Australia.
10. Department of Rehabilitation Medicine, Center of Bone Metabolism and Repair, State Key Laboratory of Trauma, Burn and Combined Injury, Daping Hospital, Third Military Medical University, Chongqing, 400042, China.
11. Department of Developmental Biology, Harvard School of Dental Medicine, Boston, MA 02115, USA.
# These authors contributed equally to this work

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Citation:
Wang K, Ren Y, Lin S, Jing Y, Ma C, Wang J, Yuan XB, Han X, Zhao H, Wang Z, Zheng M, Xiao Y, Chen L, Olsen BR, Feng JQ. Osteocytes but not osteoblasts directly build mineralized bone structures. Int J Biol Sci 2021; 17(10):2430-2448. doi:10.7150/ijbs.61012. Available from https://www.ijbs.com/v17p2430.htm

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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.

Keywords: Mineralization, osteocyte, osteoblast, DMP1, Phex, bone formation, hypophosphatemia rickets