title: Zoledronate promotes bone formation by blocking osteocyte-osteoblast communication during bone defect healing.
abstract: 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.
authors.affiliation: Department of Bone Metabolism, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, China.
authors.forename: Pingping
authors.initials: P
authors.lastname: Cui
authors.affiliation: Department of Bone Metabolism, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, China.
authors.forename: Hongrui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Bone Metabolism, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Sun
authors.affiliation: Department of Developmental Biology of Hard Tissue, Graduate School of Dental Medicine, Hokkaido University, Sapporo, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Amizuka
authors.affiliation: Department of Bone Metabolism, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, China. sunqinfeng@sdu.edu.cn.
authors.forename: Qinfeng
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Department of Bone Metabolism, School of Stomatology Shandong University, Shandong Provincial Key Laboratory of Oral Tissue Regeneration, Jinan, China. liminqi@sdu.edu.cn.
authors.forename: Minqi
authors.initials: M
authors.lastname: Li
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000469:Alkaline Phosphatase / Q000378:metabolism; D000818:Animals; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D002450:Cell Communication / Q000187:drug effects*; D018031:Connexin 43 / Q000378:metabolism; D004164:Diphosphonates / Q000494:pharmacology*; D004195:Disease Models, Animal; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D005264:Femoral Fractures / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D017102:Fracture Healing / Q000187:drug effects*; D006023:Glycoproteins / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology*; D036341:Intercellular Signaling Peptides and Proteins; D008297:Male; D051379:Mice; D010006:Osteoblasts / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010010:Osteoclasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010011:Osteocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D010012:Osteogenesis / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D000071681:Tartrate-Resistant Acid Phosphatase / Q000378:metabolism; D013997:Time Factors; D000077211:Zoledronic Acid
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D050071:Bone Density Conservation Agents; D018031:Connexin 43; D004164:Diphosphonates; C513308:Dmp1 protein, mouse; D016326:Extracellular Matrix Proteins; C543076:GJA1 protein, mouse; D006023:Glycoproteins; D007093:Imidazoles; D036341:Intercellular Signaling Peptides and Proteins; C486030:Sost protein, mouse; D000077211:Zoledronic Acid; D000469:Alkaline Phosphatase; D000071681:Tartrate-Resistant Acid Phosphatase