Osteocyte dysfunction promotes osteoarthritis through MMP13-dependent suppression of subchondral bone homeostasis

Abstract

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 the medial compartment of OA subchondral bone, with lower protease expression, diminished canalicular networks, and disorganized and hypermineralized extracellular matrix. As a step toward evaluating the causality of PLR suppression in OA, we ablated the PLR enzyme MMP13 in osteocytes while leaving chondrocytic MMP13 intact, using Cre recombinase driven by the 9.6-kb DMP1 promoter. Not only did osteocytic MMP13 deficiency suppress PLR in cortical and subchondral bone, but it also compromised cartilage. Even in the absence of injury, osteocytic MMP13 deficiency was sufficient to reduce cartilage proteoglycan content, change chondrocyte production of collagen II, aggrecan, and MMP13, and increase the incidence of cartilage lesions, consistent with early OA. Thus, in humans and mice, defects in PLR coincide with cartilage defects. Osteocyte-derived MMP13 emerges as a critical regulator of cartilage homeostasis, likely via its effects on PLR. Together, these findings implicate osteocytes in bone-cartilage crosstalk in the joint and suggest a causal role for suppressed perilacunar/canalicular remodeling in osteoarthritis.

A 3D, Dynamically Loaded Hydrogel Model of the Osteochondral Unit to Study Osteocyte Mechanobiology

“…[8,9] Osteocytes detect increased fluid flow in subchondral bone and then secrete signaling molecules that affect chondrocyte, osteoblast, and osteoclast activities that further contribute to osteochondral degeneration. [1,2,[10][11][12][13] A 3D in vitro model that recapitulates the strain and fluid flow of the osteochondral unit would enable key questions to be answered about the osteocyte's role in regulating osteochondral homeostasis and degeneration.…”

Angiogenesis stimulated by elevated PDGF-BB in subchondral bone contributes to osteoarthritis development

“…However, treatments targeting only the signaling mechanisms responsible for AC degeneration may be insufficient to halt disease progression (7,(12)(13)(14). Recent evidence suggests that pathological alterations in subchondral bone also contribute to osteoarthritis development (15)(16)(17)(18)(19)(20)(21)(22)(23).…”

Positive Feedback Regulation Between USP15 and ERK2 Promotes Cartilage Repair in Experimental Osteoarthritis

“…OA is the most common type of arthritis with in ammatory disease in the synovial joints (32,33) . It is characterized by gradual degeneration of articular cartilage and changes in the structure and function of the entire joint (34,35) . In recent years, it has been reported that the canonical SMAD signaling of the TGF-β signaling pathway contribute signi cantly to cartilage maintenance and repair.…”