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

Abstract

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.

Elevated levels of active Transforming Growth Factor β1 in the subchondral bone relate spatially to cartilage loss and impaired bone quality in human knee osteoarthritis

“…These differences in shape and orientation of the osteocyte lacune between the regions are possibly indicators of the transition process from woven to lamellar bone [24]. In addition, these results are also suggestive of dynamic active perilacunar remodelling in CA- regions, which has been reported to be a direct consequence of local osteocyte-derived TGFβ signalling [7, 12, 31-33]. Further, quantitative histological assessment (Fig.…”

“…Evidence also supports osteocytes as the most important mechano-responsive cells in bone [45], with the greatest potential to link mechanical overloading in OA to a cellular response. Interesting also, is a report that mechanosensation of subchondral bone require osteocytic TGFβ1 signalling [33] and that compressive stress changed the effect of TGFβ1 on RANKL and OPG expression in cement-oblasts and osteoblasts [46].…”

Identification of mechanics-responsive osteocyte signature in osteoarthritis subchondral bone

“…Mazur et al 36 reported that osteocytic matrix metalloproteinase 13 (MMP13) deficiency exerts a protective effect on early OA, via its effects on PLR. Bailey et al 37 verified that subchondral bone remodelling in response to injury requires osteocytic TGF-β signalling. Thus, our pioneering efforts, which obtained evidence by applying accepted concepts related to bone research and OA investigations, may reveal osteocyte-related mechanisms.…”

Sprifermin: Effects on Cartilage Homeostasis and Therapeutic Prospects in Cartilage-Related Diseases

“…( Peng et al, 2021 ). The unique structure and composition of the cartilage ECM are important factors in maintaining cartilage homeostasis, providing a smooth joint articulation and enabling articular cartilage to withstand loads several times the body weight ( Bailey et al, 2021 ; Peng et al, 2021 ). COL2 is the most abundant component in the ECM of cartilage, where it forms a fibrous network structure; while GAG absorbs a large amount of water to form gel, and thus maintaining the dilatability and elasticity of cartilage ( Sherwood et al, 2014 ).…”