Osteoarthritis is a highly prevalent and debilitating joint disorder. There is no effective medical therapy for the condition 
because of limited understanding of its pathogenesis. We show that transforming growth factor b1 (TGF-b1) is activated in 
subchondral bone in response to altered mechanical loading in an anterior cruciate ligament transection (ACLT) mouse model of 
osteoarthritis. TGF-b1 concentrations are also high in subchondral bone from humans with osteoarthritis. High concentrations 
of TGF-b1 induced formation of nestin-positive mesenchymal stem cell (MSC) clusters, leading to formation of marrow osteoid 
islets accompanied by high levels of angiogenesis. We found that transgenic expression of active TGF-b1 in osteoblastic cells 
induced osteoarthritis, whereas inhibition of TGF-b activity in subchondral bone attenuated the degeneration of articular 
cartilage. In particular, knockout of the TGF-b type II receptor (TbRII) in nestin-positive MSCs led to less development of 
osteoarthritis relative to wild-type mice after ACLT. Thus, high concentrations of active TGF-b1 in subchondral bone seem to 
initiate the pathological changes of osteoarthritis, and inhibition of this process could be a potential therapeutic approach to 
treating this disease.

Inhibition of TGF-β signaling in mesenchymal stem cells of subchondral bone attenuates osteoarthritis

Osteoarthritis (OA) is the leading cause of function loss and disability among the elderly, with significant burden on the individual and society. It is a severe disease for its high disability rates, morbidity, costs, and increased mortality. Multifactorial etiologies contribute to the occurrence and development of OA. The heterogeneous condition poses a challenge for the development of effective treatment for OA; however, emerging treatments are promising to bring benefits for OA management in the future. This narrative review will discuss recent developments of agents for the treatment of OA, including potential disease-modifying osteoarthritis drugs (DMOADs) and novel therapeutics for pain relief. This review will focus more on drugs that have been in clinical trials, as well as attractive drugs with potential applications in preclinical research. In the past few years, it has been realized that a complex interaction of multifactorial mechanisms is involved in the pathophysiology of OA. The authors believe there is no miracle therapeutic strategy fitting for all patients. OA phenotyping would be helpful for therapy selection. A variety of potential therapeutics targeting inflammation mechanisms, cellular senescence, cartilage metabolism, subchondral bone remodeling, and the peripheral nociceptive pathways are expected to reshape the landscape of OA treatment over the next few years. Precise randomized controlled trials (RCTs) are expected to identify the safety and efficacy of novel therapies targeting specific mechanisms in OA patients with specific phenotypes.

/pdf/new-trends-in-pharmacological-treatments-for-osteoarthritis-2qpjspqcxa.pdf

New Trends in Pharmacological Treatments for Osteoarthritis.

Complex molecular mechanism of ammonia-induced apoptosis in chicken peripheral blood lymphocytes: miR-27b-3p, heat shock proteins, immunosuppression, death receptor pathway, and mitochondrial pathway.

Targeted oral delivery of a drug via the intestinal lymphatic system (ILS) has the advantages of protecting against hepatic first-pass metabolism of the drug and improving its pharmacokinetic performance. It is also a promising route for the oral delivery of vaccines and therapeutic agents to induce mucosal immune responses and treat lymphatic diseases, respectively. This article describes the anatomical structures and physiological characteristics of the ILS, with an emphasis on enterocytes and microfold (M) cells, which are the main gateways for the transport of particulate delivery vehicles across the intestinal epithelium into the lymphatics. A comprehensive overview of recent advances in the rational engineering of particulate vehicles, along with the challenges and opportunities that they present for improving ILS drug delivery, is provided, and the mechanisms by which such vehicles target and transport through enterocytes or M cells are discussed. The use of naturally sourced materials, such as yeast microcapsules and their derived polymeric β-glucans, as novel ILS-targeting delivery vehicles is also reviewed. Such use is the focus of an emerging field of research. Their potential use in the oral delivery of nucleic acids, such as mRNA vaccines, is proposed.

Engineering Nano- and Microparticles as Oral Delivery Vehicles to Promote Intestinal Lymphatic Drug Transport.

The growth plate (GP) is a cartilaginous region situated between the epiphysis and metaphysis at the end of the immature long bone, which is susceptible to mechanical damage because of its vulnerable structure. Due to the limited regeneration ability of the GP, current clinical treatment strategies (e.g., bone bridge resection and fat engraftment) always result in bone bridge formation, which will cause length discrepancy and angular deformity, thus making satisfactory outcomes difficult to achieve. The introduction of cartilage repair theory and cartilage tissue engineering technology may encourage novel therapeutic approaches for GP repair using tissue engineered GPs, including biocompatible scaffolds incorporated with appropriate seed cells and growth factors. In this review, we summarize the physiological structure of GPs, the pathological process, and repair phases of GP injuries, placing greater emphasis on advanced tissue engineering strategies for GP repair. Furthermore, we also propose that three-dimensional printing technology will play a significant role in this field in the future given its advantage of bionic replication of complex structures. We predict that tissue engineering strategies will offer a significant alternative to the management of GP injuries.

/pdf/enlightenment-of-growth-plate-regeneration-based-on-8vayxjfjr6.pdf

Enlightenment of Growth Plate Regeneration Based on Cartilage Repair Theory: A Review.

Post-traumatic osteoarthritis is a prevalent debilitating joint disease. However, there is no FDA-approved disease-modifying osteoarthritis drug currently. Gene therapy can improve disease progression but lacks an effective delivery system. Here, we constructed an oral drug delivery system by non-virus-mediated interleukin-1β (IL-1β) short hairpin RNA (shRNA) and non-pathogenic yeast to evaluate its effect on osteoarthritis therapy. After recombinant IL-1β shRNA/yeast therapy, yeast microcapsule-mediated oral delivery of IL-1β shRNA greatly reduced the IL-1β expression in intestine macrophage, bone marrow macrophage, and articular cartilage, systematically regulate the inflammatory response. The degeneration of articular cartilage was significantly inhibited in the medial femoral condyle and medial tibial plateau of the knee joint. And the expression of osteoarthritis markers Col X and MMP13 was reduced in the knee joint. Thus, yeast microcapsule-mediated oral delivery of IL-1β shRNA may serve as a novel gene therapy strategy for treating joint degeneration through immunomodulation of the mononuclear phagocyte system from the intestine to subchondral bone marrow and ultimately preserving the articular cartilage joint.

Yeast microcapsule-mediated oral delivery of IL-1β shRNA for post-traumatic osteoarthritis therapy

Human osteoarthritis cartilage contains chondrocytes (OAC) and mesenchymal stromal cells (OA-MSC). Here, we found that TGF-β had different effects on OA-MSC and OAC, and revealed its lateral signaling mechanism in OA. RNAseq analysis indicated that OA-MSC expressed the same level of Bone Morphogenetic Protein (BMP) Receptor-1A as OAC but only 1/12 of Transforming Growth Factor beta (TGF-β) Receptor-1. While TGF-β specifically activated SMAD2 in OAC, it also activated BMP signaling-associated SMAD1 in OA-MSC. While TGF-β stimulated chondrogenesis in OAC, it induced hypertrophy, mineralization, and MMP-13 in OA-MSC. Inhibiting TGF-βR1 suppressed MMP-13 in OA-MSC but stimulated it in OAC. In contrast, by specifically targeting BMPR1A/ACVR1 in both cell types, LDN193189 inhibits cartilage degeneration through suppressing hypertrophy and MMP-13 in a mouse osteoarthritis model. Thus, LDN193189, a drug under development to inhibit constitutive BMP signaling during heterotopic ossification, may be re-purposed for OA treatment.

Human osteoarthritis cartilage-derived stromal cells activate joint degeneration through TGF-beta lateral signaling.

Obesity is a chronic systemic inflammatory disease, which occurs when energy intake exceeds the energy consumption. Therefore, controlling energy intake or increasing physical consumption can effectively control obesity. However, in reality, it is very difficult for the majority of obese patients to lose weight by autonomously controlling diet. In this study, oral shRNA/yeast microcapsules were constructed with non-virus-mediated IL-1β shRNA interference vectors and non-pathogenic Saccharomyces cerevisiae. Moreover, high-fat diet induced obese mice were established to assess the weight loss effect of IL-1β shRNA/yeast microcapsules via the oral route. After IL-1β shRNA/yeast treatment, body weight and fat weight was reduced. Compared with the control group, higher average food intake but lower energy conversion rate was observed in IL-1β shRNA/yeast group. In addition, lipid metabolism related cytokines and blood glucose concentration in the circulating blood was improved after IL-1β shRNA/yeast treatment. Yeast microcapsules mediated IL-1β shRNA delivery can effectively improve obesity. Noteworthy, this kind of non-diet-controlled weight loss strategy does not need diet control, and shows good biocompatibility. It is good news to obese patients who need to lose weight but cannot control their diet.

Hang Peng

Papers

Yeast microcapsule-mediated oral delivery of IL-1β shRNA for post-traumatic osteoarthritis therapy

Human osteoarthritis cartilage-derived stromal cells activate joint degeneration through TGF-beta lateral signaling.

Oral Gene Therapy of HFD-Obesity via Nonpathogenic Yeast Microcapsules Mediated shRNA Delivery.