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Glucocorticoid suppression of osteocyte perilacunar remodeling is associated with subchondral bone degeneration in osteonecrosis.

ABSTRACT: Through a process called perilacunar remodeling, bone-embedded osteocytes dynamically resorb and replace the surrounding perilacunar bone matrix to maintain mineral homeostasis. The vital canalicular networks required for osteocyte nourishment and communication, as well as the exquisitely organized bone extracellular matrix, also depend upon perilacunar remodeling. Nonetheless, many questions remain about the regulation of perilacunar remodeling and its role in skeletal disease. Here, we find that suppression of osteocyte-driven perilacunar remodeling, a fundamental cellular mechanism, plays a critical role in the glucocorticoid-induced osteonecrosis. In glucocorticoid-treated mice, we find that glucocorticoids coordinately suppress expression of several proteases required for perilacunar remodeling while causing degeneration of the osteocyte lacunocanalicular network, collagen disorganization, and matrix hypermineralization; all of which are apparent in human osteonecrotic lesions. Thus, osteocyte-mediated perilacunar remodeling maintains bone homeostasis, is dysregulated in skeletal disease, and may represent an attractive therapeutic target for the treatment of osteonecrosis.

SUBMITTER: Fowler TW

PROVIDER: S-EPMC5361115 | biostudies-literature | 2017 Mar

REPOSITORIES: biostudies-literature

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Glucocorticoid suppression of osteocyte perilacunar remodeling is associated with subchondral bone degeneration in osteonecrosis.

Fowler Tristan W TW Acevedo Claire C Mazur Courtney M CM Hall-Glenn Faith F Fields Aaron J AJ Bale Hrishikesh A HA Ritchie Robert O RO Lotz Jeffrey C JC Vail Thomas P TP Alliston Tamara T

Scientific reports 20170322

Through a process called perilacunar remodeling, bone-embedded osteocytes dynamically resorb and replace the surrounding perilacunar bone matrix to maintain mineral homeostasis. The vital canalicular networks required for osteocyte nourishment and communication, as well as the exquisitely organized bone extracellular matrix, also depend upon perilacunar remodeling. Nonetheless, many questions remain about the regulation of perilacunar remodeling and its role in skeletal disease. Here, we find th ...[more]

PMID: 28327602

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Project description:Bone fragility fractures are caused by low bone mass or impaired bone quality. Osteoblast/osteoclast coordination determines bone mass, but the factors that control bone quality are poorly understood. Osteocytes regulate osteoblast and osteoclast activity on bone surfaces but can also directly reorganize the bone matrix to improve bone quality through perilacunar/canalicular remodeling; however, the molecular mechanisms remain unclear. We previously found that deleting the transcriptional regulators Yes-associated protein (YAP) and transcriptional co-activator with PDZ-motif (TAZ) from osteoblast-lineage cells caused lethality in mice due to skeletal fragility. Here, we tested the hypothesis that YAP and TAZ regulate osteocyte-mediated bone remodeling by conditional ablation of both YAP and TAZ from mouse osteocytes using 8 kb-DMP1-Cre. Osteocyte-conditional YAP/TAZ deletion reduced bone mass and dysregulated matrix collagen content and organization, which together decreased bone mechanical properties. Further, YAP/TAZ deletion impaired osteocyte perilacunar/canalicular remodeling by reducing canalicular network density, length, and branching, as well as perilacunar flourochrome-labeled mineral deposition. Consistent with recent studies identifying TGF-β as a key inducer of osteocyte expression of matrix-remodeling enzymes, YAP/TAZ deletion in vivo decreased osteocyte expression of matrix proteases MMP13, MMP14, and CTSK. In vitro, pharmacologic inhibition of YAP/TAZ transcriptional activity in osteocyte-like cells abrogated TGF-β-induced matrix protease gene expression. Together, these data show that YAP and TAZ control bone matrix accrual, organization, and mechanical properties by regulating osteocyte-mediated bone remodeling. Elucidating the signaling pathways that control perilacunar/canalicular remodeling may enable future therapeutic targeting of bone quality to reverse skeletal fragility. © 2019 American Society for Bone and Mineral Research.

Project description:Subchondral sclerosis is considered the main characteristic of advanced osteoarthritis, in which bone remodeling mediated by transforming growth factor β (TGFβ) signaling plays an indispensable role in the metabolism. Osteocytes have been identified as pivotal regulators of bone metabolism, due to their mechanosensing and endocrine function. Therefore, the aim of the present study was to investigate the association between osteocyte TGFβ signal and subchondral sclerosis. Knee tibia plateau samples were collected from osteoarthritic patients and divided into three groups: The full cartilage, partial cartilage and full defect groups. Next, changes in osteocyte TGFβ signaling and subchondral bone structure underlying various types of cartilage erosion were detected. Bone mineral density (BMD) assay, histology [hematoxylin and eosin, Safranin‑O/Fast green, and tartrate resistant acid phosphatase (TRAP) staining], and reverse transcription‑quantitative PCR mainly detected structural alterations, osteogenic and osteoclastic activity in the cartilage and subchondral bone. The activation of the TGFβ signaling pathway in the subchondral bone was detected by immunohistochemistry and western blotting. The association between osteocyte TGFβ and the regulation of bone metabolism was analyzed by correlation analysis, and further proven in vitro. It was confirmed that the BMD of the subchondral bone increased and underwent sclerosis in the partial cartilage and full defect groups. Additional observation included the thinning of the area of calcified cartilage, in which a bone island formed locally, with subchondral bone plate thickening and increased trabecular bone volume. TRAP staining suggested an increase in bone resorption in subchondral underlying areas of the partial cartilage and full defect groups. Immunohistochemistry results confirmed the activation of osteocyte TGFβ in subchondral underlying areas with severe cartilage erosion. Moreover, osteocyte phosphorylated‑Smad2/3 was positively correlated with subchondral BMD, alkaline phosphatase and osteopontin mRNA expression, but it was negatively correlated with TRAP+ cells. Furthermore, it was confirmed in vitro that osteocyte TGFβ signaling could regulate the osteogenic and osteoclastic activity of the mesenchymal stem cells. This study illustrated that osteocyte TGFβ signaling is positively associated with the remodeling of subchondral bone in advanced osteoarthritis and provides a preliminary theoretical basis for further investigations of the role and mechanism of osteocyte TGFβ in subchondral of osteoarthritis.

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Dataset Information

Glucocorticoid suppression of osteocyte perilacunar remodeling is associated with subchondral bone degeneration in osteonecrosis.

Publications

Glucocorticoid suppression of osteocyte perilacunar remodeling is associated with subchondral bone degeneration in osteonecrosis.

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