Osteocyte Dysfunction in Joint Homeostasis and Osteoarthritis

Abstract

Structural disturbances of the subchondral bone are a hallmark of osteoarthritis (OA), including sclerotic changes, cystic lesions, and osteophyte formation. Osteocytes act as mechanosensory units for the micro-cracks in response to mechanical loading. Once stimulated, osteocytes initiate the reparative process by recruiting bone-resorbing cells and bone-forming cells to maintain bone homeostasis. Osteocyte-expressed sclerostin is known as a negative regulator of bone formation through Wnt signaling and the RANKL pathway. In this review, we will summarize current understandings of osteocytes at the crossroad of allometry and mechanobiology to exploit the relationship between osteocyte morphology and function in the context of joint aging and osteoarthritis. We also aimed to summarize the osteocyte dysfunction and its link with structural and functional disturbances of the osteoarthritic subchondral bone at the molecular level. Compared with normal bones, the osteoarthritic subchondral bone is characterized by a higher bone volume fraction, a larger trabecular bone number in the load-bearing region, and an increase in thickness of pre-existing trabeculae. This may relate to the aberrant expressions of sclerostin, periostin, dentin matrix protein 1, matrix extracellular phosphoglycoprotein, insulin-like growth factor 1, and transforming growth factor-beta, among others. The number of osteocyte lacunae embedded in OA bone is also significantly higher, yet the volume of individual lacuna is relatively smaller, which could suggest abnormal metabolism in association with allometry. The remarkably lower percentage of sclerostin-positive osteocytes, together with clustering of Runx-2 positive pre-osteoblasts, may suggest altered regulation of osteoblast differentiation and osteoblast-osteocyte transformation affected by both signaling molecules and the extracellular matrix. Aberrant osteocyte morphology and function, along with anomalies in molecular signaling mechanisms, might explain in part, if not all, the pre-osteoblast clustering and the uncoupled bone remodeling in OA subchondral bone.

Theaflavin-3,3 ′ -Digallate Protects Cartilage from Degradation by Modulating Inflammation and Antioxidant Pathways

“…According to the literature, the occurrence of OA depends on a variety of mechanisms. In addition to inflammatory responses, mechanical load, oxidative stress, and cell senescence may all promote the degradation and inhibit the synthesis of the extracellular matrix, resulting in cartilage damage and ultimately OA [36][37][38][39]. Therefore, early suppression of inflammatory responses in chondrocytes and mitigation of oxidative stress levels may delay the onset of OA.…”

Dickkopf‑3 and β‑catenin play opposite roles in the Wnt/β‑catenin pathway during the abnormal subchondral bone formation of human knee osteoarthritis

“…Previous research has characterized early-stage OA with increased subchondral bone remodeling and late OA with decreased bone resorption and increased bone formation ( 5 ). Abnormal subchondral bone remodeling and osteophyte formation are hallmarks of OA progression ( 20 ).…”

"Hematopoietic Elements in Osteoarthritic Femurs Compared to Normal Bone Marrow as Evaluated by Immunohistochemistry"

“…Breakdown of cartilage and subchondral bone may allow for exchange of larger-than-normal molecules to influence signaling pathways and increase cross-talk between the normally unconnected compartments of synovium and bone marrow [19]. Studies have shown cellular fractions such as macrophages, osteoblasts, osteocytes, adipocytes, T-cells, B-cells, megakaryocytes, granulocytes, and osteoblasts found in the bone/bone marrow may affect, or be affected by, the cartilage and subchondral bone changes seen in OA joints [10][11][12][13][14][15][16][17][18].…”

“…The degenerative changes which include thinning of cartilage layers, increase in subchondral bone content, increased underlying bone remodeling, and fissures which penetrate both cartilage and bone have been well documented [2][3][4][5][6][7][8][9]. Qualitative and quantitative studies have evaluated adipocyte, T-cell, B-cell, macrophage, megakaryocyte, granulocyte, osteoblast, osteoclast, and osteocyte activity that affects the cartilage and subchondral bone in OA [10][11][12][13][14][15][16][17][18]. The goal of the study was to evaluate the hematopoietic elements in the proximal end of the osteoarthritic femur head as they compare to hematopoietic elements in normal bone marrow aspirates collected from the traditional posterior iliac crest to determine whether the joint pressure and bone degeneration influences the underlying blood cell fractions.…”