MDA-9/Syntenin in the tumor and microenvironment defines prostate cancer bone metastasis.

Bone metastasis is a frequent and incurable consequence of advanced prostate cancer (PC). An interplay between disseminated tumor cells and heterogeneous bone resident cells in the metastatic niche initiates this process. Melanoma differentiation associated gene-9 (mda-9/Syntenin/syndecan binding protein) is a prometastatic gene expressed in multiple organs, including bone marrow-derived mesenchymal stromal cells (BM-MSCs), under both physiological and pathological conditions. We demonstrate that PDGF-AA secreted by tumor cells induces CXCL5 expression in BM-MSCs by suppressing MDA-9-dependent YAP/MST signaling. CXCL5-derived tumor cell proliferation and immune suppression are consequences of the MDA-9/CXCL5 signaling axis, promoting PC disease progression. mda-9 knockout tumor cells express less PDGF-AA and do not develop bone metastases. Our data document a previously undefined role of MDA-9/Syntenin in the tumor and microenvironment in regulating PC bone metastasis. This study provides a framework for translational strategies to ameliorate health complications and morbidity associated with advanced PC.

Bone marrow stromal cells generate an osteoinductive microenvironment when cultured on titanium-aluminum-vanadium substrates with biomimetic multiscale surface roughness.

Osseointegration of titanium-based implants possessing complex macroscale/microscale/mesoscale/nanoscale (multiscale) topographies support a direct and functional connection with native bone tissue by promoting recruitment, attachment and osteoblastic differentiation of bone marrow stromal cells (MSCs). Recent studies show that the MSCs on these surfaces produce factors, including bone morphogenetic protein 2 (BMP2) that can cause MSCs not on the surface to undergo osteoblast differentiation, suggesting they may produce an osteogenic environmentin vivo. This study examined if soluble factors produced by MSCs in contact with titanium-aluminum-vanadium (Ti6Al4V) implants possessing a complex multiscale biomimetic topography are able to induce osteogenesis ectopically. Ti6Al4V disks were grit-blasted and acid-etched to create surfaces possessing macroscale and microscale roughness (MM), micro/meso/nanoscale topography (MN), and macro/micro/meso/nanoscale topography (MMNTM). Polyether-ether-ketone (PEEK) disks were also fabricated by machining to medical-grade specifications. Surface properties were assessed by scanning electron microscopy, contact angle, optical profilometry, and x-ray photoelectron spectroscopy. MSCs were cultured in growth media (GM). Proteins and local factors in their conditioned media (CM) were measured on days 4, 8, 10 and 14: osteocalcin, osteopontin, osteoprotegerin, BMP2, BMP4, and cytokines interleukins 6, 4 and 10 (IL6, IL4, and IL10). CM was collected from D14 MSCs on MMNTMand tissue culture polystyrene (TCPS) and lyophilized. Gel capsules containing active demineralized bone matrix (DBM), heat-inactivated DBM (iDBM), and iDBM + MMN-GM were implanted bilaterally in the gastrocnemius of athymic nude mice (N= 8 capsules/group). Controls included iDBM + GM; iDBM + TCPS-CM from D5 to D10 MSCs; iDBM + MMN-CM from D5 to D10; and iDBM + rhBMP2 (R&D Systems) at a concentration similar to D5-D10 production of MSCs on MMNTMsurfaces. Legs were harvested at 35D. Bone formation was assessed by micro computed tomography and histomorphometry (hematoxylin and eosin staining) with the histology scored according to ASTM 2529-13. DNA was greatest on PEEK at all time points; DNA was lowest on MN at early time points, but increased with time. Cells on PEEK exhibited small changes in differentiation with reduced production of BMP2. Osteoblast differentiation was greatest on the MN and MMNTM, reflecting increased production of BMP2 and BMP4. Pro-regenerative cytokines IL4 and IL10 were increased on Ti-based surfaces; IL6 was reduced compared to PEEK. None of the media from TCPS cultures was osteoinductive. However, MMN-CM exhibited increased bone formation compared to iDBM and iDBM + rhBMP2. Furthermore, exogenous rhBMP2 alone, at the concentration found in MMN-CM collected from D5 to D10 cultures, failed to induce new bone, indicating that other factors in the CM play a critical role in that osteoinductive microenvironment. MSCs cultured on MMNTMTi6Al4V surfaces differentiate and produce an increase in local factors, including BMP2, and the CM from these cultures can induce ectopic bone formation compared to control groups, indicating that the increased bone formation arises from the local response by MSCs to a biomimetic, multiscale surface topography.

Hydrophilic implants generated using a low-cost dielectric barrier discharge plasma device at the time of placement exhibit increased osseointegration in an animal pre-clinical study: An effect that is sex-dependent.

OBJECTIVES: Increased wettability of titanium and titanium alloy surfaces due to processing and storage methods increases osteoprogenitor cell differentiation and osseointegration compared to microroughness alone. Implants that are exposed to air have a hydrophobic surface due to adsorption of atmospheric hydrocarbons, which can limit overall implant success. Dielectric barrier discharge plasma (DBD) is one method to increase surface hydrophilicity. Although current DBD methods yield a hydrophilic surface, adsorbed hydrocarbons rapidly restore hydrophobicity. We demonstrated that application of DBD to implants previously packaged in a vacuum, generates a hydrophilic surface that supports osteoblastic differentiation in vitro and this can be done immediately prior to use. In the present study, we tested the hypothesis that DBD treatment to alter surface wettability at the time of implant placement will improve osseointegration in vivo. MATERIALS AND METHODS: Twenty male and sixteen female rabbits were used in a preclinical trans-axial femur model of osseointegration. Control and DBD treatment implants were inserted randomized per hind limb in each rabbit (1 implant/hind-limb). At 6 weeks post-surgery, bone-to-implant contact, adjacent bone volume, and torque to failure were assessed by micro-CT, calcified histology, and mechanical testing. RESULTS: DBD plasma treatment of vacuum-sealed implants increased surface wettability and did not change surface chemistry or roughness. Peak torque and torsional energy, and bone-to-implant contact increased with DBD treatment in males. In contrast, female rabbits showed increased osseointegration equal to DBD treated male implants regardless of DBD plasma treatment. CONCLUSION: DBD treatment is an effective method to enhance osseointegration by increasing surface wettability; however, this response is sex dependent. In healthy female patients, DBD treatment may not be necessary but in older patients or patients with compromised bone, this treatment could be an effective measure to ensure implant success.