ObjectivesAfter an injury, the biological reattachment of tendon to bone is a challenge because healing takes place between a soft (tendon) and a hard (bone) tissue. Even after healing, the transition zone in the enthesis is not completely regenerated, making it susceptible to re-injury. In this study, we aimed to regenerate Achilles tendon entheses (ATEs) in wounded rats using a combination of kartogenin (KGN) and platelet-rich plasma (PRP).MethodsWounds created in rat ATEs were given three different treatments: kartogenin platelet-rich plasma (KGN-PRP); PRP; or saline (control), followed by histological and immunochemical analyses, and mechanical testing of the rat ATEs after three months of healing.ResultsHistological analysis showed well organised arrangement of collagen fibres and proteoglycan formation in the wounded ATEs in the KGN-PRP group. Furthermore, immunohistochemical analysis revealed fibrocartilage formation in the KGN-PRP-treated ATEs, evidenced by the presence of both collagen I and II in the healed ATE. Larger positively stained collagen III areas were found in both PRP and saline groups than those in the KGN-PRP group. Chondrocyte-related genes, SOX9 and collagen II, and tenocyte-related genes, collagen I and scleraxis (SCX), were also upregulated by KGN-PRP. Moreover, mechanical testing results showed higher ultimate tensile strength in the KGN-PRP group than in the saline control group. In contrast, PRP treatment appeared to have healed the injured ATE but induced no apparent formation of fibrocartilage. The saline-treated group showed poor healing without fibrocartilage tissue formation in the ATEs.ConclusionsOur results show that injection of KGN-PRP induces fibrocartilage formation in the wounded rat ATEs. Hence, KGN-PRP may be a clinically relevant, biological approach to regenerate injured enthesis effectively.Cite this article: J. Zhang, T. Yuan, N. Zheng, Y. Zhou, M. V. Hogan, J. H-C. Wang. The combined use of kartogenin and platelet-rich plasma promotes fibrocartilage formation in the wounded rat Achilles tendon entheses. Bone Joint Res 2017;6:231–244. DOI: 10.1302/2046-3758.64.BJR-2017-0268.R1.

The combination of docetaxel with a RANKL-inhibiting agent merits further investigation for treatment of advance PCa.

Platelet-rich plasma (PRP) has become a popular option for the treatment of injured tendons. However, the efficacy of PRP treatment is a matter of heated debate in orthopaedics and sports medicine. In this study, we used a cell culture model to evaluate the potential effects of PRP treatment on degenerative tendinopathy. The in vitro model, which uses the current concept of "diseases-in-adish", consisted of tendon stem/progenitor cells (TSCs) that were derived from rabbit tendons and cultured in differentiating media with and without autologous platelet-rich clot releasate (PRCR). We found that 10% PRCR treatment of TSCs blocked their non-tenogenic differentiation, as evidenced by the marked decrease in lipid droplets, proteoglycan accumulation, and calcium deposition on cell surfaces. Moreover, the protein markers for non-tenocytes (adiponectin, collagen type II, and osteocalcin) were either minimally expressed or greatly reduced. However, after TSCs underwent non-tenogenic differentiation by pre-treatment in non-tenogenic media for two days, PRCR only slightly reduced adipogenesis and osteogenesis of TSCs, although chondrogenesis was markedly suppressed. Finally, PRCR treatment after pretreatment of TSCs in non-tenogenic media for one week had little effect on any of the three nontenogenic differentiations of TSCs. These findings suggest that the injection of PRP in clinics may not be able to effectively reverse the degenerative conditions of late-stage tendinopathy, which are characterized by lipid depositions, proteoglycan accumulation, and calcification, either alone or in combination.

The propagation of HIV-1 is driven in part by cell-to-cell transmission most frequently observed in dendritic cells (DC) and their subsets-one of the earliest immune cells likely to encounter HIV-1 during acute infection at mucosal surfaces. DCs are capable of highly effective viral transfer to target CD4+ T-cells across the virological synapse, a specialised virus-induced cell junction, which enables widespread viral dissemination and accelerated disease progression. Our previous findings have implicated a major role for cytokines and chemokines in the infection and transmission of HIV-1 from DC subsets, though a global study of their molecular functions has yet to be completed. In this study, we screened 319 individual genes using the Human ON-TARGET plus SMARTpool cytokine & chemokine siRNA library to investigate the differential effects on HIV-1 transfer from monocyte-derived DCs (MDDC) to a CD4+ SupT1 T-lymphoblastic cell line. Using integrative, data-driven approaches we successfully identified several cytokine superfamilies with potent restrictive properties against HIV-1 trans-infection from MDDC to SupT1. The activities of these candidates were validated using three key loss-of-function assays including genetic downregulation, neutralisation by biologics and pharmacological inhibition in trans-to both SupT1 and autologous CD4+ T-cells. Disruption of specific cytokine-driven mechanisms in MDDC results in dramatic changes in the capacity for cell-to-cell transfer to CD4+ T-cells. These findings add to a growing body of evidence linking the cytokine network which will inform novel therapeutic strategies against early-stage HIV-1 infection and transmission

In the cutaneous microenvironment, interactions between mast cells (MCs) and sensory neurons play an important role in immune responses. Neuropeptides such as neurokinin A and substance P direct MC function by initiating signaling through neurokinin (NKRs) receptors, and Mas related G-protein receptors (Mrgpr)s. Recent studies highlight the importance of the MrgprB2 (mouse) and MrgprX2 (human) in the MC response to pseudo-allergens, secretagogues and substance P. To date, a relationship between NKRs and the MrgprB2/X2 has not been investigated. In this study, we hypothesize that MrgprB2/X2 is transciptionally controlled by the NK2R and its high affinity ligand, neurokinin A. In mice, we show that administration of neurokinin A diminishes MrgprB2 RNA expression. Surprisingly, NK2R antagonism also downregulates MrgprB2 expression and MrgprB2 expression is markedly diminished in mice lacking the NK2R. In contrast, co-administration of neurokinin A and an NK2R antagonist increases MrgprB2 expression. The MC response to the canonical MrgprB2 ligand, compound 48/80, mirrored the changes in MrgprB2 transcript expression. In human skin explants, NK2R antagonism had minimal effect on MrgprX2 expression, but co-administration of neurokinin A and a NK2R antagonist markedly upregulated MrgprX2 expression, as seen in murine skin. These data demonstrate that the NK2R-signaling influences MrgprB2/ X2 expression and, that in absence of the NK2R, neurokinin A interacts with an unknown receptor to increase MrpgrB2/X2 expression. Collectively, these data uncover a novel role for NK2R signaling in the regulation of MrgprB2/X2. These important findings have implications for patients with mast cell mediated cutanous inflammatory diseases.