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Alliston, T.

Publications and source records attributed to Alliston, T..

2 recordsLinked to original sources
bioRxiv2019

CYLD, a Mechanosensitive Deubiquitinase, Regulates TGFβ for Load-induced Bone Formation and Mediates PGE2-dependent Repression of TGFβ Signaling in Osteocytes

Many signaling pathways involved in bone homeostasis also participate in the anabolic response of bone to mechanical loading. For example, TGF{beta} signaling coordinates the maintenance of bone mass and bone quality through its effects on osteoblasts, osteoclasts, and osteocytes. TGF{beta} signaling is also essential for the mechanosensitive formation of new bone. However, the mechanosensitive mechanisms controlling TGF{beta} signaling in osteocytes remain to be determined, particularly those that integrate TGF{beta} signaling with other early responses to mechanical stimulation. Here, we used an in vivo mouse hindlimb loading model to identify mechanosensitive molecules in the TGF{beta} pathway, and MLOY4 cells to evaluate their interactions with the prostaglandin E2 (PGE2) pathway, which is well-known for its rapid response to mechanical stimulation and its role in bone anabolism. Although mRNA levels for several TGF{beta} ligands, receptors, and effectors were unchanged, the level of phosphorylated Smad3 (pSmad3) was reduced in tibial bone as early as 3 hrs after early mechanical stimulation. We found that PGE2 and its receptor, EP2, repress pSmad3 levels and transactivation of Serpine1 in osteocytes. PGE2 and EP2 control the level of pSmad3 through a proteasome-dependent mechanism that relies on the deubiquitinase CYLD. CYLD protein levels were also reduced in the tibiae within 3 hrs of mechanical loading. Using CYLD-deficient mice, we found that CYLD is required for the rapid load-mediated repression of pSmad3 and for load-induced bone formation. These data introduce CYLD as a mechanosensitive deubiquitinase that participates in the PGE2-dependent repression of TGF{beta} signaling in osteocytes.

molecular biology↗
bioRxiv2019

Suppressed Osteocyte Perilacunar / Canalicular RemodelingPlays a Causal Role in Osteoarthritis

Osteoarthritis (OA), long considered a primary disorder of articular cartilage, is commonly associated with subchondral bone sclerosis. However, the cellular mechanisms responsible for changes to subchondral bone in OA, and the extent to which these changes are drivers of or a secondary reaction to cartilage degeneration, remain unclear. In knee joints from human patients with end-stage OA, we found evidence of profound defects in osteocyte function. Suppression of osteocyte perilacunar/canalicular remodeling (PLR) was most severe in OA subchondral bone, with lower protease expression, diminished canalicular networks, and disorganized and hypermineralized extracellular matrix. To determine if PLR suppression plays a causal role in OA, we ablated the PLR enzyme MMP13 in osteocytes, while leaving chondrocytic MMP13 intact. Not only did osteocytic MMP13 deficiency suppress PLR in cortical and subchondral bone, but it also compromised cartilage. Even in the absence of injury, this osteocyte-intrinsic PLR defect was sufficient to reduce cartilage proteoglycan content and increase the incidence of cartilage lesions, consistent with early OA. Thus, in humans and mice, osteocyte PLR is a critical regulator of cartilage homeostasis. Together, these findings implicate osteocytes in bone-cartilage crosstalk in the joint and identify the causal role of suppressed perilacunar/canalicular remodeling in osteoarthritis.

physiology↗