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Mechanosensitive Control of Articular Cartilage and Subchondral Bone Homeostasis in Mice Requires Osteocytic Transforming Growth Factor β Signaling
Author(s) -
Bailey Karsyn N.,
Nguyen Jeffrey,
Yee Cristal S.,
Dole Neha S.,
Dang Alexis,
Alliston Tamara
Publication year - 2021
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.41548
Subject(s) - sclerostin , endocrinology , medicine , homeostasis , cartilage , osteoarthritis , transforming growth factor , sox9 , signal transduction , chemistry , anatomy , pathology , microbiology and biotechnology , biology , wnt signaling pathway , transcription factor , biochemistry , alternative medicine , gene
Objective Transforming growth factor β (TGFβ) signaling plays a complex tissue‐specific and nonlinear role in osteoarthritis (OA). This study was conducted to determine the osteocytic contributions of TGFβ signaling to OA. Methods To identify the role of osteocytic TGFβ signaling in joint homeostasis, we used 16‐week‐old male mice (n = 9–11 per group) and female mice (n = 7–11 per group) with an osteocyte‐intrinsic ablation of TGFβ receptor type II (TβRII ocy−/− mice) and assessed defects in cartilage degeneration, subchondral bone plate (SBP) thickness, and SBP sclerostin expression. To further investigate these mechanisms in 16‐week‐old male mice, we perturbed joint homeostasis by subjecting 8‐week‐old mice to medial meniscal/ligamentous injury (MLI), which preferentially disrupts the mechanical environment of the medial joint to induce OA. Results In all contexts, independent of sex, genotype, or medial or lateral joint compartment, increased SBP thickness and SBP sclerostin expression were spatially associated with cartilage degeneration. Male TβRII ocy−/− mice, but not female TβRII ocy−/− mice, had increased cartilage degeneration, increased SBP thickness, and higher levels of SBP sclerostin compared with control mice (all P < 0.05), demonstrating that the role of osteocytic TGFβ signaling on joint homeostasis is sexually dimorphic. With changes in joint mechanics following injury, control mice had increased SBP thickness, subchondral bone volume, and SBP sclerostin expression (all P < 0.05). TβRII ocy−/− mice, however, were insensitive to subchondral bone changes with injury, suggesting that mechanosensation at the SBP requires osteocytic TGFβ signaling. Conclusion Our results provide new evidence that osteocytic TGFβ signaling is required for a mechanosensitive response to injury, and that osteocytes control SBP homeostasis to maintain cartilage health, identifying osteocytic TGFβ signaling as a novel therapeutic target for OA.