Supplemental Digital Content is Available in the Text. Peripheral high mobility group box 1 promotes joint pain through TLR4 activation in immune cells that is strongly evident in male but not female mice.

Several bone conditions, eg, bone cancer, osteoporosis, and rheumatoid arthritis (RA), are associated with a risk of developing persistent pain. Increased osteoclast activity is often the hallmark of these bony pathologies and not only leads to bone remodeling but is also a source of pronociceptive factors that sensitize the bone-innervating nociceptors. Although historically bone loss in RA has been believed to be a consequence of inflammation, both bone erosion and pain can occur years before the symptom onset. Here, we have addressed the disconnection between inflammation, pain, and bone erosion by using a combination of 2 monoclonal antibodies isolated from B cells of patients with RA. We have found that mice injected with B02/B09 monoclonal antibodies (mAbs) developed a long-lasting mechanical hypersensitivity that was accompanied by bone erosion in the absence of joint edema or synovitis. Intriguingly, we have noted a lack of analgesic effect of naproxen and a moderate elevation of few inflammatory factors in the ankle joints suggesting that B02/B09-induced pain-like behavior does not depend on inflammatory processes. By contrast, we found that inhibiting osteoclast activity and acid-sensing ion channel 3 signaling prevented the development of B02/B09-mediated mechanical hypersensitivity. Moreover, we have identified secretory phospholipase A2 and lysophosphatidylcholine 16:0 as critical components of B02/B09-induced pain-like behavior and shown that treatment with a secretory phospholipase A2 inhibitor reversed B02/B09-induced mechanical hypersensitivity and bone erosion. Taken together, our study suggests a potential link between bone erosion and pain in a state of subclinical inflammation and offers a step forward in understanding the mechanisms of bone pain in diseases such as RA.

Supplemental Digital Content is Available in the Text. Disulfide high mobility group box 1 protein activates microglia and induces pain-like behavior in male and female mice, but the mechanisms underlying its central pronociceptive effects are sex-dependent.

Extracellular vesicles (EVs), spherical bilayered proteolipids, behave as paracrine effectors since they are released from cells to deliver signals to other cells. They control a diverse range of biological processes by transferring proteins, lipids, and nucleic acids between cells and are secreted by a wide spectrum of cell types and are found in various biological fluids. EVs are formed at the plasma membrane or in endosomes and are heterogeneous in size and composition. Increasing understanding of the working mechanisms is promising for therapeutic and diagnostic opportunities. In this review, we will focus on the recent developments in this emerging field with special emphasis on the role of EVs in the bone microenvironment, with a central role for the osteoblasts in the communication with a diversity of cells, including bone metastases.

Cartilage repair by bone marrow derived mesenchymal stem cells (MSCs) can be influenced by inflammation in the knee. Next to synovium, the infrapatellar fat pad (IPFP) has been described as a source for inflammatory factors. Here, we investigated whether factors secreted by the IPFP affect chondrogenesis of MSCs and whether this is influenced by different joint pathologies or obesity. Furthermore, we examined the role of IPFP resident macrophages. First, we made conditioned medium from IPFP obtained from osteoarthritic joints, IPFP from traumatically injured joints during anterior cruciate ligament reconstruction, and subcutaneous adipose tissue. Additionally, we made conditioned medium of macrophages isolated from osteoarthritic IPFP and of polarised monocytes from peripheral blood. We evaluated the effect of different types of conditioned medium on MSC chondrogenesis. Conditioned medium from IPFP decreased collagen 2 and aggrecan gene expression as well as thionin and collagen type 2 staining. This antichondrogenic effect was the same for conditioned medium from IPFP of osteoarthritic and traumatically injured joints. Furthermore, IPFP from obese (Body Mass Index >30) donors did not inhibit chondrogenesis more than that of lean (Body Mass Index <25) donors. Finally, conditioned medium from macrophages isolated from IPFP decreased the expression of hyaline cartilage genes, as did peripheral blood monocytes stimulated with pro-inflammatory cytokines. The IPFP and the resident pro-inflammatory macrophages could therefore be targets for therapies to improve MSC-based cartilage repair.