The expression of osteopontin (OPN), CD44 variants, and integrins has been correlated with tumorigenesis and metastasis. Here we show that these proteins cooperate to enhance cell motility. First, we demonstrate that several different CD44 variants bind to OPN in an arginine-glycineaspartic acid-independent manner, but that the standard form of CD44 does not. These CD44 variants bind to both the amino- and COOH-terminal portions of OPN independently of the arginine-glycine-aspartic acid sequence, suggesting that multiple domains on OPN can be bound by the CD44 variants. Antibodies directed against the integrin beta1 subunit are able to inhibit this binding. The binding of CD44 variants to OPN is significantly augmented by both anti-CD44s and anti-CD44v antibodies. This augmentation by anti-CD44 antibodies is OPN specific and, again, can be blocked by anti-beta1 antibodies. Finally, we show that OPN binding by CD44 variants/beta1-containing integrins promotes cell spreading, motility, and chemotactic behavior.

CD44 variants but not CD44s cooperate with _1-containing′ integrins′ to permit cells to osteopontin independently of arginine-′ glycine-aspartic acid, thereby stimulating cell motility and′ chemotaxis.

Osteopontin (OPN) also known by its official gene designation secreted phosphoprotein‐1 (SPP1) is a fascinating, multifunctional protein expressed in a number of cell types that functions not only in intercellular communication, but also in the extracellular matrix (ECM). OPN/SPP1 possesses cytokine, chemokine, and signal transduction functions by virtue of modular structural motifs that provide interaction surfaces for integrins and CD44‐variant receptors. In humans, there are three experimentally verified splice variants of OPN/SPP1 and CD44’s ten exons are also alternatively spiced in a cell/tissue‐specific manner, although very little is known about how this is regulated in the central nervous system (CNS). Post‐translational modifications of phosphorylation, glycosylation, and localized cleavage by specific proteases in the cells and tissues where OPN/SPP1 functions, provides additional layers of specificity. However, the former make elucidating the exact molecular mechanisms of OPN/SPP1 function more complex. Flexibility in OPN/SPP1 structure and its engagement with integrins having the ability to transmit signals in inside‐out and outside‐in direction, is likely why OPN/SPP1 can serve as an early detector of inflammation and ongoing tissue damage in response to cancer, stroke, traumatic brain injury, pathogenic infection, and neurodegeneration, processes that impair tissue homeostasis. This review will focus on what is currently known about OPN/SPP1 function in the brain.

https://onlinelibrary.wiley.com/doi/pdfdirect/10.1111/imr.13081

Osteopontin/secreted phosphoprotein‐1 harnesses glial‐, immune‐, and neuronal cell ligand‐receptor interactions to sense and regulate acute and chronic neuroinflammation

The possibility of engineering, testing, and deploying a cybernetic interface to the visual areas of the human brain has inspired scientists, biomedical engineers, clinicians, and science fiction writers. Implemented as a cortical visual prosthesis, visual perception might be provided to individuals with blindness. Based upon pioneering work in the late 1960’s, and the development of significant technology throughout the remainder of the twentieth century, the Intracortical Visual Prosthesis (ICVP) is being planned for clinical trial. Autonomous, wireless, 16-channel stimulator modules will be used to tile the dorsolateral surface of the human occipital lobe. Each module will contain 16 intracortical electrodes that penetrate the cortical surface and provide simulation currents to visual processing areas of the brain. Through the use of spatial and temporal integration, the expectation is that the brain will convert the artificial visual information into useful visual perceptions. While it is not expected that the ICVP will produce normal vision, prior work strongly suggests that the artificial visual perception may notably enhance the user’s ability to recognize objects and navigate, and improve overall quality of life.

The Intracortical Visual Prosthesis Project

Circulating full-length osteopontin (FL-OPN) is elevated in plasma from patients with various infectious diseases, such as adult T-cell leukemia, Mycobacterium tuberculosis (TB), hepatitis virus infection, leptospirosis, acquired immune deficiency syndrome (AIDS), AIDS/TB, and coronavirus disease 2019 (COVID-19). Proteolysis of OPN by thrombin, matrix metalloproteases, caspase 8/3, cathepsin D, plasmin, and enterokinase generates various cleaved OPNs with a variety of bioactivities by binding to different target cells. Moreover, OPN is susceptible to gradual proteolysis. During inflammation, one of the cleaved fragments, N-terminal thrombin-cleaved OPN (trOPN or OPN-Arg168 [OPN-R]), induces dendritic cell (DC) adhesion. Further cleavage by carboxypeptidase B2 or carboxypeptidase N removes Arg168 from OPN-R to OPN-Leu167 (OPN-L). Consequently, OPN-L decreases DC adhesion. In particular, the differences in plasma level over time are observed between FL-OPN and its cleaved OPNs during inflammation. We found that the undefined OPN levels (mixture of FL-OPN and cleaved OPN) were elevated in plasma and reflected the pathology of TB and COVID-19 rather than FL-OPN. These infections are associated with elevated levels of various proteases. Inhibition of the cleavage or the activities of cleaved products may improve the outcome of the therapy. Research on the metabolism of OPN is expected to create new therapies against infectious diseases.

https://www.mdpi.com/2227-9059/9/8/1006/pdf

Both Full-Length and Protease-Cleaved Products of Osteopontin Are Elevated in Infectious Diseases.

: This project is to perform translational research tasks needed to prepare an intracortical visual prosthesis (ICVP) for testing in a human No human trial testing of the prosthesis will occur under the funded work Preparatory tasks include final maturation of the implantable hardware, pre FDA IDE testing of the ICVP in non-human primates, reliability and biocompatibility testing, development of a human testing protocol, development of a human volunteer selection and assessment protocol, preparation of an investigation device exemption application (IDE) to the FDA Progress to-date has been somewhat hampered by delayed approval of the psychology testing protocols (human subjects), and the animal testing protocols (non-human primates), by the USARMYMC However, all protocol approvals have now been obtained This delay has also slowed the spending of funds for these areas within the first year The work focused on technology maturation has been highly productive Sample stimulator units have been subjected to brutal environmental testing with 100% survival Larger numbers of stimulator units are in the process of being constructed to provide statistical power for the environmental testing Following the human protocol acceptances, work has commenced at both IIT and Johns Hopkins for the development of the testing and assessment protocols A graduate student from IIT has initiated work within the laboratory of Dr Dagnelie at JHU Analysis of interview data from the earlier Dobelle visual prosthesis recipients has already yielded valuable insight about the volunteer recruitment and participation process Sixteen publications and presentations have resulted from the funded work, and several publications are in preparation While the project is projected for a 1-year no-cost extension request, due to the slow start-up, it is anticipated that by the end of the project all parts of the SOW will be complete, with the ICVP ready for clinical testing in a human trial

Preparation for the Implantation of an Intracortical Visual Prosthesis in a Human

The advent of Human Immunodeficiency Virus (HIV) antiretrovirals have reduced the severity of HIV related neurological comorbidities but they nevertheless remain prevalent. Synaptic degeneration due to the action of several viral factors released from infected brain myeloid and glia cells and inflammatory cytokines has been attributed to the manifestation of a range of cognitive and behavioral deficits. The contributions of specific pro-inflammatory factors and their interplay with viral factors in the setting of treatment and persistence are incompletely understood. Exposure of neurons to chemokine receptor-4(CXCR4)-tropic HIV-1 envelope glycoprotein (Env) can lead to post-synaptic degradation of dendritic spines. The contribution of members of the extracellular matrix (ECM) and specifically, of perineuronal nets (PNN) toward synaptic degeneration, is not fully known, even though these structures are found to be disrupted in post-mortem HIV-infected brains. Osteopontin (Opn, gene name SPP1), a cytokine-like protein, is found in abundance in the HIV-infected brain. In this study, we investigated the role of Opn and its ECM integrin receptors, β1- and β3 integrin in modifying neuronal synaptic sculpting. We found that in hippocampal neurons incubated with HIV-1 Env protein and recombinant Opn, post-synaptic-95 (PSD-95) puncta were significantly increased and distributed to dendritic spines when compared to Env-only treated neurons. This effect was mediated through β3 integrin, as silencing of this receptor abrogated the increase in post-synaptic spines. Silencing of β1 integrin, however, did not block the increase of post-synaptic spines in hippocampal cultures treated with Opn. However, a decrease in the PNN to βIII-tubulin ratio was found, indicating an increased capacity to support spine growth. From these results, we conclude that one of the mechanisms by which Opn counters the damaging impact of the HIV Env protein on hippocampal post-synaptic plasticity is through complex interactions between Opn and components of the ECM which activate downstream protective signaling pathways that help maintain the potential for effective post-synaptic plasticity.

Osteopontin and Integrin Mediated Modulation of Post-Synapses in HIV Envelope Glycoprotein Exposed Hippocampal Neurons

Development of Mapping Methods with Simulated Phosphenes for Implementation in Intracortical Visual Prosthesis Recipients

/pdf/correction-to-osteopontin-secreted-phosphoprotein-1-behaves-4lzzhlst5w.pdf

Correction to: Osteopontin/secreted phosphoprotein-1 behaves as a molecular brake regulating the neuroinflammatory response to chronic viral infection (Journal of Neuroinflammation, (2020), 17, 1, (273), 10.1186/s12974-020-01949-4)

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Osteopontin and Integrin Mediated Modulation of Post-Synapses in HIV Envelope Glycoprotein Exposed Hippocampal Neurons

Development of Mapping Methods with Simulated Phosphenes for Implementation in Intracortical Visual Prosthesis Recipients

Correction to: Osteopontin/secreted phosphoprotein-1 behaves as a molecular brake regulating the neuroinflammatory response to chronic viral infection (Journal of Neuroinflammation, (2020), 17, 1, (273), 10.1186/s12974-020-01949-4)