Zoledronate promotes bone formation by blocking osteocyte-osteoblast communication during bone defect healing
Pingping Cui1, Hongrui Liu1, Jing Sun1, Norio Amizuka2, Qinfeng Sun1 and Minqi Li1
1Department of Bone Metabolism, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, China and 2Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan
Offprint requests to: Qinfeng Sun, DDS, PhD, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Wenhua West Road 44-1, Jinan 250012, China. e-mail: sunqinfeng@sdu.edu.cn or Minqi Li, DDS, PhD, Department of Bone Metabolism, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Wenhua West Road 44-1, Jinan 250012, China. e-mail: liminqi@sdu.edu.cn
Summary. Nitrogen-containing bisphosphonates (N-BPs) are potent antiresorptive drugs and their actions on osteoclasts have been studied extensively. Recent studies have suggested that N-BPs also target bone-forming cells. However, the precise mechanism of N-BPs in osteoblasts is paradoxical, and the specific role of osteocytes is worthy of in-depth study. Here, we investigated the cellular mechanisms of N-BPs regulating bone defect healing by zoledronate (ZA). Bone histomorphometry confirmed an increase in new bone formation by systemic ZA administration. ZA induced more alkaline phosphatase-positive osteoblasts and tartrate-resistant acid phosphatase-positive osteoclasts residing on the bone surface. Inexplicably, ZA increased SOST expression in osteocytes embedded in the bone matrix, which was not compatible with the intense osteoblast activity on the bone surface. ZA induced heterogeneous osteocytes and disturbed the distribution of the osteocytic-canalicular system (OLCS). Furthermore, according to the degree of OLCS regularity, dentin matrix protein 1 reactivity had accumulated around osteocytes in the ZA group, but it was distributed evenly in the OLCS of the control group. The control group showed a dense array of the gap junction protein connexin 43. However, connexin 43 was extremely sparse after ZA administration. In summary, ZA treatment reduces gap junction connections and blocks cellular communication between osteocytes and osteoblasts. Retaining SOST expression in osteocytes leads to activation of the Wnt signaling pathway and subsequent bone formation. Histol Histopathol 33, 89-99 (2018)
Key words: Zoledronate, Osteoblasts, Osteocytes, Connexin 43, Bone defect
DOI: 10.14670/HH-11-893