Osteoblast Function Is Compromised at Sites of Focal Bone Erosion in Inflammatory Arthritis

Abstract

In rheumatoid arthritis (RA), synovial inflammation results in focal erosion of articular bone. Despite treatment attenuating inflammation, repair of erosions with adequate formation of new bone is uncommon in RA, suggesting that bone formation may be compromised at these sites. Dynamic bone histomorphometry was used in a murine model of RA to determine the impact of inflammation on osteoblast function within eroded arthritic bone. Bone formation rates at bone surfaces adjacent to inflammation were similar to those observed in nonarthritic bone; therefore, osteoblast activity is unlikely to compensate for the increased bone resorption at these sites. Within arthritic bone, the extent of actively mineralizing surface was reduced at bone surfaces adjacent to inflammation compared with bone surfaces adjacent to normal marrow. Consistent with the reduction in mineralized bone formation, there was a notable paucity of cells expressing the mid-to late stage osteoblast lineage marker alkaline phosphatase, despite a clear presence of cells expressing the early osteoblast lineage marker Runx2. In addition, several members of the Dickkopf and secreted Frizzled-related protein families of Wnt signaling antagonists were upregulated in arthritic synovial tissues, suggesting that inhibition of Wnt signaling could be one mechanism contributing to impaired osteoblast function within arthritic bone. Together, these data indicate that the presence of inflammation within arthritic bone impairs osteoblast capacity to form adequate mineralized bone, thus contributing to the net loss of bone and failure of bone repair at sites of focal bone erosion in RA.

Glucocorticoids and Tumor Necrosis Factor α Increase Oxidative Stress and Suppress Wnt Protein Signaling in Osteoblasts

“…Moreover, administration of GCs or an endogenous rise in TNF␣ has been causally linked to increased osteoclast numbers, decreased osteoblast numbers, and bone loss (1,50). However, the molecular mechanisms responsible for the deleterious effects of GCs or TNF␣ on bone have not been fully elucidated.…”

Histone deacetylases (HDAC) in physiological and pathological bone remodelling

“…In pathological bone loss, there is an uncoupling of bone formation and resorptive processes leading to excessive bone loss. While diseases such as osteoporosis, periodontitis, RA and multiple myeloma are characterised by enhanced osteoclast resorption there are also reports of reduced osteoblast bone formation [60][61][62]. For this reason, osteoblasts have been targeted with anabolic agents including parathyroid hormone (PTH), bone morphogenetic proteins (BMPs), as well as sclerostin neutralising antibody, in order to stimulate bone formation [63].…”

“…In animal models of inflammatory arthritis and in human RA tissues, large multinucleated osteoclastic cells that resorb the subchondral bone, have been detected at sites of bone loss in synovial joints [40,[95][96][97]. Normal osteoblast function is impaired in arthritis, at sites of focal bone erosions, with reduced formation of mineralised bone at sites adjacent to synovial inflammation [60]. In these tissues, there was an abundance of cells expressing the early osteoblast marker Runx2, but these same cells did not express ALP and osteocalcin, suggesting that these cells were immature osteoblasts [60].…”

IL-12 Family Cytokines in Inflammation and Bone Erosion of Rheumatoid Arthritis

“…In RA, this response is significantly dampened in areas of inflammation when compared with healthy areas bone (Walsh and Gravallese, 2010). This indicates that cell signaling for osteoblast maturation is suppressed in inflammatory sites (Walsh et al, 2009). In healthy bone, osteoblast precursor expresses Runx2 and leads to full maturation of non-proliferative osteoblasts with expression of alkaline phosphatase, collagens and mineralization cell matrix proteins -such as osteocalcin, osteopontin and bone salioprotein (Komori, 2010).…”

“…Wnt protein receptors have been identified as Frizzlrd (FZD) and low density lipoprotein receptor-related protein 5 and 6 (LRP5/6) (Takahashi et al, 2011). Osteoblasts produce endogenous inhibitors, such Dickkopf1 (DKK1), to competitively bind to LRP5 and LRP6 (Walsh et al, 2009). TNF stimulates DKK1 production and therefore suppresses osteoblast development (Diarra et al, 2007).…”