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

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.

Effect of non-enzymatic glycation on collagen nanoscale mechanisms in diabetic and age-related bone fragility

Age and diabetes have long been known to induce an oxidative reaction between glucose and collagen,leading to the accumulation of advanced glycation end-products(AGEs)cross-links in collagenous tissues.More recently,AGEs content has been related to loss of bone quality,independent of bone mass,and increased fracture risk with aging and diabetes.Loss of bone quality is mostly attributed to changes in material properties,structural organization,or cellular remodeling.Though all these factors play a role in bone fragility disease,some common recurring patterns can be found between diabetic and age-related bone fragility.The main pattern we will discuss in this viewpoint is the increase of fibrillar collagen stiffness and loss of collagen-induced plasticity with AGE accumulation.This study focused on recent related experimental studies and discusses the correlation between fluorescent AGEs content at the molecular and fibrillar scales,collagen deformation mechanisms at the nanoscale,and resistance to bone fracture at the macroscale.