Mechanosensitive Control of Articular Cartilage and Subchondral Bone Homeostasis in Mice Requires Osteocytic Transforming Growth Factor β Signaling

Autor: Jeffrey Nguyen, Tamara Alliston, Karsyn N. Bailey, Alexis Dang, Neha S. Dole, Cristal S. Yee
Rok vydání: 2020
Předmět:
0301 basic medicine
Cartilage
Articular
Male
Aging
Mechanotransduction
Osteoarthritis
Mechanotransduction
Cellular
Menisci
Tibial
chemistry.chemical_compound
Mice
0302 clinical medicine
Transforming Growth Factor beta
2.1 Biological and endogenous factors
Immunology and Allergy
Medicine
Homeostasis
Aetiology
Medial Collateral Ligament
Mice
Knockout
Joint compartment
Adaptor Proteins
Hindlimb
medicine.anatomical_structure
Tibial
Public Health and Health Services
Mechanosensitive channels
Female
Receptor
Signal Transduction
medicine.medical_specialty
Knockout
Clinical Sciences
Immunology
Medial Collateral Ligament
Knee
030209 endocrinology & metabolism
Osteocytes
Bone and Bones
Article
03 medical and health sciences
Sex Factors
Rheumatology
Internal medicine
Animals
Knee
Adaptor Proteins
Signal Transducing
Mechanosensation
business.industry
Arthritis
Cartilage
Signal Transducing
Receptor
Transforming Growth Factor-beta Type II
X-Ray Microtomography
medicine.disease
Arthritis & Rheumatology
030104 developmental biology
Endocrinology
chemistry
Musculoskeletal
Menisci
Sclerostin
Cellular
business
Articular
Transforming Growth Factor-beta Type II
Transforming growth factor
Zdroj: Arthritis Rheumatol
Arthritis & rheumatology (Hoboken, N.J.), vol 73, iss 3
ISSN: 2326-5205
Popis: 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 (TβRIIocy-/- 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 TβRIIocy-/- mice, but not female TβRIIocy-/- 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). TβRIIocy-/- 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.
Databáze: OpenAIRE
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