Efficacy of an oral collagen therapy compared with intra-articular therapies (hyaluronic acid and platelet-rich plasma) to treat knee osteoarthritis / Eficacia de una terapia oral de colágeno comparada con terapias intraarticulares (ácido hialurónico y plasma rico en plaquetas) en el manejo de la osteoartritis de rodilla

Introducción: la osteoartritis es una enfermedad crónica y progresiva que afecta a más del 30 % de las personas mayores de 60 años. Actualmente, se reconoce la osteoartritis como una enfermedad multifactorial. Se emplean varios tratamientos conservadores en el manejo de la osteoartritis de rodilla (AINE, analgésicos y terapias intraarticulares). Se realizó un ensayo clínico aleatorizado para determinar si una terapia a base de 10 g de colágeno hidrolizado y 100 mg de fucoidano (Hydroidan pro, Acten, Suiza) era más efectiva que las terapias intraarticulares. Métodos: se dividió a los pacientes en 3 grupos. El primero recibió 23 g de ACTEN® cada día durante 3 meses. Los otros grupos recibieron una única inyección intraarticular de ácido hialurónico (5 ml) o plasma rico en plaquetas (3 ml). Se emplearon las escalas WOMAC, SF-12 y VAS para valorar el dolor al inicio, 4, 12 y 24 semanas después. Resultados: se incluyó a 108 pacientes con osteoartritis de rodilla de grado II-III que participaron en un estudio de seguimiento de 24 semanas de duración. La edad media fue de 57 años (53-65). Los 3 grupos rebajaron la puntuación en el grupo WOMAC (p < 0,001). El grupo que recibió colágeno y fucoidano obtuvo puntuaciones más bajas en las escalas WOMAC y VAS que los grupos que recibieron ácido hialurónico y plasma rico en plaquetas a las 24 semanas (p < 0,001). Conclusiones: el colágeno y el fucoidano tomado por vía oral, a diario, y durante 12 semanas parecen cosechar mejores resultados en las escalas WOMAC y VAS que las terapias intraarticulares a base de ácido hialurónico o plasma rico en plaquetas. Se debería de intentarse combinar terapias orales e intraarticulares para determinar su perfil de eficacia.(AU)

Introduction: osteoarthritis is a chronic and progressive disease. It affects over 30 % of people older than 60. Osteoarthri-tis is currently recognized as a multifactorial disease. Various conservative treatments are used in the management of kneeosteoarthritis (NSAIDs, analgesics, and intra-articular therapy). We conducted a randomized clinical trial to determine if a10 g therapy of hydrolyzed collagen along with 100 mg fucoidan (Hydroidan pro, Acten, Switzerland) is more effective thanintra-articular therapies.Methods: we divided patients into 3 groups. The first group received 23 g of ACTEN®, daily, for 3 months. The other groupsreceived a single intra-articular injection of hyaluronic acid (5 ml) or platelet-rich plasma (3 ml). We used the WOMAC scale,the SF-12 scale, and the VAS for pain at baseline, and 4, 12, and 24 weeks later.Results: we enrolled 108 patients with grade II-III knee osteoarthritis who underwent a 24-week follow-up study. The meanage was 57 years (53-65). The three groups showed low scores in the WOMAC group (p < 0.001). The collagen with fucoid-an group had lower WOMAC and VAS scores compared with the hyaluronic acid and platelet-rich plasma groups at 24weeks (p < 0.001).Conclusions: collagen along with fucoidan taken orally, daily, for 12 weeks seem to have better results in the WOMACand VAS scales compared with intra-articular therapies such as hyaluronic acid or platelet-rich plasma. Combined oral andintra-articular therapies should be tried to determine their efficacy profile.(AU)

Oral Ingestion of AP Collagen Peptide Leads to Systemic Absorption of Gly-Pro-Hyp, Alleviating H2O2-Induced Dermal Fibroblast Aging.

Collagen-derived dipeptides and tripeptides have various physiological activities. In this study, we compared the plasma kinetics of free Hyp, peptide-derived Hyp, Pro-Hyp, cyclo(Pro-Hyp), Hyp-Gly, Gly-Pro-Hyp, and Gly-Pro-Ala after ingestion of four different collagen samples: AP collagen peptide (APCP), general collagen peptide, collagen, and APCP and γ-aminobutyric acid (GABA) combination. Each peptide was measured by high-performance liquid chromatography and triple quadrupole mass spectrometer. We found that, among all the peptides that were analyzed, only Gly-Pro-Hyp was significantly increased after ingestion of APCP compared with that of general collagen peptides and collagen. In addition, ingestion of the APCP and GABA combination improved the absorption efficiency of Gly-Pro-Ala. Finally, we reveal that Gly-Pro-Hyp was effective for preventing H2O2-induced reduction in extracellular matrix (ECM)-related genes, COL1A, elastin, and fibronectin, in dermal fibroblasts. Taken together, APCP significantly enhances the absorption of Gly-Pro-Hyp, which might act as an ECM-associated signaling factor in dermal fibroblasts, and the APCP and GABA combination promotes Gly-Pro-Ala absorption. Clinical Trial Registration number: UMIN000047972.

Tolerability and efficacy assessment of an oral collagen supplement for the improvement of biophysical and ultrasonographic parameters of skin in middle eastern consumers.

BACKGROUND: Topical skin care products often do not reach the deeper layers of the skin, and oral hydrolyzed collagen is one of the newest and most popular systemic supplementations for skin rejuvenation. However, there are limited information in case of Middle Eastern consumers OBJECTIVE: The purpose of this study was to evaluate the tolerability and efficacy of an oral collagen supplement for improvement of skin elasticity, hydration, and roughness in Middle Eastern consumers. METHODS AND MATERIALS: It was a 12-week, before-after clinical study, conducted on 20 participants (18 women and 2 men) aged 44.15 ± 5.36 years with skin type III-IV. Skin elasticity parameters (R0, R2, R5, and R7), skin hydration and friction, as well as the thickness and echo density of the dermis, were measured after six and 12 weeks daily intake of the study product, as well as 4 weeks after stopping its use (week 16). Participants' satisfaction was assessed on the basis of their answers to the standard questionnaire, and tolerability of the product was assessed by monitoring the adverse effects. RESULTS: A significant improvement was detected in R2, R5, and skin friction at week 12 (p-values 0.041, 0.012 and <0.01, respectively). At week 16, the values remained at an increased level, which indicates the persistence of the results. The increase of dermis density in week 16 was also significant (p-value = 0.03). Moderate overall satisfaction was reported with the treatment, and a few gastrointestinal complications were reported. CONCLUSION: The study demonstrated that oral collagen peptides could significantly improve the skin elasticity, roughness, and dermis echo density, and they also proved to be safe and well-tolerated.

Tratamiento mediante suplementación oral o fármacos sistémicos del envejecimiento cutáneo. Revisión narrativa de la literatura / Oral Supplementation and Systemic Drugs for Skin Aging: A Narrative Review

El envejecimiento cutáneo está influido por factores intrínsecos y extrínsecos y múltiples mecanismos patogénicos están involucrados. Los tratamientos utilizados en la actualidad son sobre todo tópicos o son procedimientos mínimamente invasivos. La evidencia sobre la utilidad de la terapia sistémica es limitada: los estudios son en su mayoría de pequeño tamaño, de reducida duración, incluyen a mujeres de manera mayoritaria, la metodología de evaluación es heterogénea y no hay parámetros consensuados de respuesta clínica relevante. Además, los suplementos o fármacos sistémicos no están exentos de efectos adversos. El colágeno hidrolizado oral y el ácido hialurónico oral son bien tolerados y múltiples ensayos clínicos muestran que pueden mitigar algunos signos de envejecimiento cutáneo. La isotretinoína oral en dosis bajas es otra alternativa, pero con un mayor potencial de efectos adversos. Múltiples suplementos, como vitaminas, flavonoides, diversos extractos de plantas y oligoelementos, presentan escasa evidencia clínica. El futuro del manejo del envejecimiento cutáneo parece ser el tratamiento con agentes senolíticos o senomórficos dirigidos específicamente contra células cutáneas senescentes. (AU)

Skin aging is influenced by intrinsic and extrinsic factors and involves multiple pathogenic mechanisms. The most widely used treatments are topical products and minimally invasive procedures. Evidence on the benefits of systemic therapy is limited for several reasons: Reliance on mostly small and predominantly female samples, short study durations, methodologic heterogeneity, and a lack of consensus on which outcome measures are clinically relevant. Furthermore, systemic drugs and oral supplements are not without adverse effects. Oral hydrolyzed collagen and oral hyaluronic acid are well tolerated, and numerous clinical trials show they can mitigate some signs of skin aging. Low-dose oral isotretinoin is another option, but it has a higher risk of adverse effects. Evidence is lacking on the effects of the many dietary supplements on offer, such as vitamins, flavonoids, plant extracts, and trace elements. The future of skin aging management would appear to lie in the use of senolytic and senomorphic agents targeting senescent cells in the skin. (AU)

[Translated article] Oral Supplementation and Systemic Drugs for Skin Aging: A Narrative Review / Tratamiento mediante suplementación oral o fármacos sistémicos del envejecimiento cutáneo. Revisión narrativa de la literatura

Skin aging is influenced by intrinsic and extrinsic factors and involves multiple pathogenic mechanisms. The most widely used treatments are topical products and minimally invasive procedures. Evidence on the benefits of systemic therapy is limited for several reasons: reliance on mostly small and predominantly female samples, short study durations, methodologic heterogeneity, and a lack of consensus on which outcome measures are clinically relevant. Furthermore, systemic drugs and oral supplements are not without adverse effects. Oral hydrolyzed collagen and oral hyaluronic acid are well tolerated, and numerous clinical trials show they can mitigate some signs of skin aging. Low-dose oral isotretinoin is another option, but it has a higher risk of adverse effects. Evidence is lacking on the effects of the many dietary supplements on offer, such as vitamins, flavonoids, plant extracts, and trace elements. The future of skin aging management would appear to lie in the use of senolytic and senomorphic agents targeting senescent cells in the skin. (AU)

El envejecimiento cutáneo está influido por factores intrínsecos y extrínsecos y múltiples mecanismos patogénicos están involucrados. Los tratamientos utilizados en la actualidad son sobre todo tópicos o son procedimientos mínimamente invasivos. La evidencia sobre la utilidad de la terapia sistémica es limitada: los estudios son en su mayoría de pequeño tamaño, de reducida duración, incluyen a mujeres de manera mayoritaria, la metodología de evaluación es heterogénea y no hay parámetros consensuados de respuesta clínica relevante. Además, los suplementos o fármacos sistémicos no están exentos de efectos adversos. El colágeno hidrolizado oral y el ácido hialurónico oral son bien tolerados y múltiples ensayos clínicos muestran que pueden mitigar algunos signos de envejecimiento cutáneo. La isotretinoína oral en dosis bajas es otra alternativa, pero con un mayor potencial de efectos adversos. Múltiples suplementos, como vitaminas, flavonoides, diversos extractos de plantas y oligoelementos presentan escasa evidencia clínica. El futuro del manejo del envejecimiento cutáneo parece ser el tratamiento con agentes senolíticos o senomórficos dirigidos específicamente contra células cutáneas senescentes. (AU)

Long-acting microneedle patch loaded with adipose collagen fragment for preventing the skin photoaging in mice.

Skin photoaging is one of the most serious public health problems in the 21st century that may lead to thin, saggy, and structurally weakened skin. Adipokine therapy toward skin photoaging is always associated with poor permeability, biologic stability and the short in vivo release duration. Our laboratory previously extracted an extracellular matrix component of adipose tissue by purely physical methods, namely "adipose collagen fragment (ACF)", which holds promise for preventing skin photoaging. However, the injection treatment of ACF requires repeated preparation processes and injection procedures, which may be time-consuming and painful. Therefore, we describe the fabrication and assessment of a detachable ACF-microneedle (ACF-MN) patch that creates minimally invasive dermal microtrauma upon application. And we evaluated the morphology characterization, mechanical properties and puncture performance in vitro. The delivery efficiency of ACF from the patches was estimated in vitro and vivo. Then, the therapeutic efficacy was identified through applying ACF-MN patches into the dermis of UVA-induced photoaging mice and the related detection of skin photoaging was estimated. Our results demonstrated that ACF-MN exhibited well skin puncture performance and could release ACF component slowly. Meanwhile, this microneedle device loaded with ACF exhibited the treatment efficiency on skin photoaging in a mouse model. Therefore, implantation of the microtrauma-mediated, long-acting ACF-MN system can be utilized as a potential candidate for preventing skin photoaging in the clinic.

Endogenously produced catecholamines improve the regulatory function of TLR9-activated B cells.

The sympathetic nervous system (SNS) contributes to immune balance by promoting anti-inflammatory B cells. However, whether B cells possess a self-regulating mechanism by which they modulate regulatory B cell (Breg) function is not well understood. In this study, we investigated the ability of B cells to synthesize their own catecholamines upon stimulation with different B cell activators and found that expression of the enzyme tyrosine hydroxylase (TH), required to generate catecholamines, is up-regulated by Toll-like receptor (TLR)9. This TLR9-dependent expression of TH correlated with up-regulation of adrenergic receptors (ADRs), enhanced interleukin (IL)-10 production, and overexpression of the co-inhibitory ligands programmed death ligand 1 (PD-L1) and Fas ligand (FasL). Moreover, concomitant stimulation of ß1-3-ADRs together with a B cell receptor (BCR)/TLR9 stimulus clearly enhances the anti-inflammatory potential of Bregs to suppress CD4 T cells, a crucial population in the pathogenesis of autoimmune diseases, like rheumatoid arthritis (RA). Furthermore, TH up-regulation was also demonstrated in B cells during the course of collagen-induced arthritis (CIA), a mouse model for the investigation of RA. In conclusion, our data show that B cells possess an autonomous mechanism to modulate their regulatory function in an autocrine and/or paracrine manner. These findings help to better understand the function of B cells in the regulation of autoimmune diseases and the interplay of SNS.

Collagen Peptides, in Association with Vitamin C, Sodium Hyaluronate, Manganese and Copper, as Part of the Rehabilitation Project in the Treatment of Chronic Low Back Pain.

BACKGROUND AND OBJECTIVE: Low back pain (LBP) is a frequent symptom. Among the causes that can determine it, lumbar osteoarthritis plays an important role. Therapeutic exercise, according to McKenzie method, has been shown to be effective in the treatment of LBP. Oral supplementation with collagen peptides represents a new therapeutic possibility in osteoarthritis. The aim of this study is to evaluate the combined efficacy of therapeutic exercise and oral administered viscosupplements in the treatment of osteoarthritis-related chronic LBP. METHODS: Sixty patients were recruited and randomly divided into two groups (Group A and B). Group A performed only kinesitherapy, Group B carried out the same kinesitherapy combined with the daily administration of food supplements such as Fortigel®, Vitamin C, sodium hyaluronate, manganese and copper, during the whole treatment period. Patients were evaluated at the time of recruitment (T0), at the end of the treatment (T1 - 3 weeks after T0) and 6 weeks after T1 (T2). The outcome measures used were: Visual Analogue Scale (VAS), Oswestry Disability Index (ODI), and Short Form-12 (SF-12). RESULTS: All the outcomes improved significantly at T1 in both groups, but more markedly in group B. Furthermore, in group A at T2, there was a statistically significant worsening in the scores of VAS, ODI and physical component of the SF-12, while in group B, this variation has not been detected. CONCLUSION: The combination of rehabilitation based on McKenzie back exercises and oral viscosupplementation with Fortigel®, Vitamin C, sodium hyaluronate, manganese and copper represents a valid option in patients with chronic LBP, as it ensures pain relief and improvement in the quality of life and in lumbar spine functionality. These therapeutic benefits are more evident and long-lasting compared to those obtained with rehabilitation alone.

Algae Metabolites as an Alternative in Prevention and Treatment of Skin Problems Associated with Solar Radiation and Conventional Photo-protection

Abstract The histological structure and biochemistry of the skin is affected by solar radiation having adverse effects ranging from sunburns, premature aging that includes wrinkles, spots, dryness, and loss of collagen to cancer development. The skin has defense mechanisms to prevent damage caused by radiation, but when radiation exposure is excessive these mechanisms are not strong enough to protect the skin. The use of sunscreen is the most common practice of photo- protection. The active ingredients of these cosmetic protective formulations are generally from synthetic origin and have presented several drawbacks at the level of photo-stability, systemic absorption and can generate contact and photo-contact dermatitis. This review illustrates skin solar radiation problems, common sunscreen ingredients limitation and mentions how algae can be an alternative according to studies that have evaluated the photo-protective potential of extracts and compounds isolated by different techniques.

Oral Intake of Enzymatically Decomposed AP Collagen Peptides Improves Skin Moisture and Ceramide and Natural Moisturizing Factor Contents in the Stratum Corneum.

The stratum corneum (SC) is the outermost layer of the epidermis and plays an important role in maintaining skin moisture and protecting the skin from the external environment. Ceramide and natural moisturizing factor (NMF) are the major SC components that maintain skin moisture. In this study, we investigated whether the oral intake of enzymatically decomposed AP collagen peptides (APCPs) can improve skin moisture and barrier function by assessing changes in the ceramide and NMF contents in the SC after APCP ingestion with the aim to develop a skin functional food. Fifty participants orally ingested APCP (1000 mg) or placebo for 12 weeks, and then, skin hydration and skin texture were evaluated. SC samples were collected to analyze skin scaling, ceramide, and NMF contents. Participants in the APCP group exhibited improved skin moisture content by 7.33% (p = 0.031) and roughness by -4.09% (p = 0.036) when compared with those in the placebo group. NMF content; the amounts of amino acids (AA), including glycine and proline; and AA derivatives were significantly increased in the APCP group (31.98 µg/mg protein) compared to those in the placebo group (-16.01 µg/mg protein) (p = 0.006). The amounts of total ceramides and ceramide subclasses were significantly higher in the APCP group than in the placebo group (p = 0.014). In conclusion, our results demonstrate that APCP intake improves skin moisture and increase the ceramide and NMF contents in the SC, thereby enhancing the skin barrier function.

Addressing the Osteoporosis Problem-Multifunctional Injectable Hybrid Materials for Controlling Local Bone Tissue Remodeling.

Novel multifunctional biomimetic injectable hybrid systems were synthesized. The physicochemical as well as biological in vitro and in vivo tests demonstrated that they are promising candidates for bone tissue regeneration. The hybrids are composed of a biopolymeric collagen/chitosan/hyaluronic acid matrix and amine group-functionalized silica particles decorated with apatite to which the alendronate molecules were coordinated. The components of these systems were integrated and stabilized by cross-linking with genipin, a compound of natural origin. They can be precisely injected into the diseased tissue in the form of a viscous sol or a partially cross-linked hydrogel, where they can serve as scaffolds for locally controlled bone tissue regeneration/remodeling by supporting the osteoblast formation/proliferation and maintaining the optimal osteoclast level. These materials lack systemic toxicity. They can be particularly useful for the repair of small osteoporotic bone defects.

Proteoglycan Combined with Hyaluronic Acid and Hydrolyzed Collagen Restores the Skin Barrier in Mild Atopic Dermatitis and Dry, Eczema-Prone Skin: A Pilot Study.

Dry and eczema-prone skin conditions such as atopic dermatitis and xerotic eczema primarily indicate an impaired skin barrier function, which leads to chronic pruritus. Here, we investigated the effects of a novel emollient containing H.ECMTM liposome, which contains a soluble proteoglycan in combination with hydrolyzed collagen and hyaluronic acid. A prospective, single-arm study was conducted on 25 participants with mild atopic dermatitis or dry skin to assess the hydration and anti-inflammatory effect of the novel emollient applied daily over four weeks. All efficacy parameters, including itching severity, transepidermal water loss, and skin hydration, improved significantly after four weeks. The in vitro and ex vivo studies confirmed the restoration of the skin's barrier function. The study revealed the clinical and laboratory efficacy of H.ECMTM liposome in reducing itching and improving the skin's barrier integrity. Thus, the use of H.ECMTM liposome can be considered a therapeutic option for dry and eczema-prone skin.

Evaluation of Therapeutic Collagen-Based Biomaterials in the Infarcted Mouse Heart by Extracellular Matrix Targeted MALDI Imaging Mass Spectrometry.

The goal of this study was to develop strategies to localize human collagen-based hydrogels within an infarcted mouse heart, as well as analyze its impact on endogenous extracellular matrix (ECM) remodeling. Collagen is a natural polymer that is abundantly used in bioengineered hydrogels because of its biocompatibility, cell permeability, and biodegradability. However, without the use of tagging techniques, collagen peptides derived from hydrogels can be difficult to differentiate from the endogenous ECM within tissues. Imaging mass spectrometry is a robust tool capable of visualizing synthetic and natural polymeric molecular structures yet is largely underutilized in the field of biomaterials outside of surface characterization. In this study, our group leveraged a recently developed matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) technique to enzymatically target collagen and other ECM peptides within the tissue microenvironment that are both endogenous and hydrogel-derived. Using a multimodal approach of fluorescence microscopy and ECM-IMS techniques, we were able to visualize and relatively quantify significantly abundant collagen peptides in an infarcted mouse heart that were localized to regions of therapeutic hydrogel injection sites. On-tissue MALDI MS/MS was used to putatively identify sites of collagen peptide hydroxyproline site occupancy, a post-translational modification that is critical in collagen triple helical stability. Additionally, the technique could putatively identify over 35 endogenously expressed ECM peptides that were expressed in hydrogel-injected mouse hearts. Our findings show evidence for the use of MALDI-IMS in assessing the therapeutic application of collagen-based biomaterials.

Immunohistochemical Evaluation of Periodontal Regeneration Using a Porous Collagen Scaffold.

(1) Aim: To immunohistochemically evaluate the effect of a volume-stable collagen scaffold (VCMX) on periodontal regeneration. (2) Methods: In eight beagle dogs, acute two-wall intrabony defects were treated with open flap debridement either with VCMX (test) or without (control). After 12 weeks, eight defects out of four animals were processed for paraffin histology and immunohistochemistry. (3) Results: All defects (four test + four control) revealed periodontal regeneration with cementum and bone formation. VCMX remnants were integrated in bone, periodontal ligament (PDL), and cementum. No differences in immunohistochemical labeling patterns were observed between test and control sites. New bone and cementum were labeled for bone sialoprotein, while the regenerated PDL was labeled for periostin and collagen type 1. Cytokeratin-positive epithelial cell rests of Malassez were detected in 50% of the defects. The regenerated PDL demonstrated a larger blood vessel area at the test (14.48% ± 3.52%) than at control sites (8.04% ± 1.85%, p = 0.0007). The number of blood vessels was higher in the regenerated PDL (test + control) compared to the pristine one (p = 0.012). The cell proliferative index was not statistically significantly different in pristine and regenerated PDL. (4) Conclusions: The data suggest a positive effect of VCMX on angiogenesis and an equally high cell turnover in the regenerated and pristine PDL. This VCMX supported periodontal regeneration in intrabony defects.

IgD promotes pannus formation by activating Wnt5A-Fzd5-CTHRC1-NF-κB signaling pathway in FLS of CIA rats and the regulation of IgD-Fc-Ig fusion protein.

Rheumatoid arthritis (RA) is a systemic autoimmune disease characterized by joint inflammation, synovial hyperplasia, cartilage degeneration, bone erosion, and pannus. Immunoglobulin D (IgD) plays an important role in autoimmune diseases although the content of it in vivo is low. Increased concentrations of anti-IgD autoantibodies have been detected in many RA patients. IgD-Fc-Ig fusion protein is constructed by connecting human IgD Fc domain and IgG1 Fc domain, which specifically block the IgD/ IgDR pathway and regulate the function of cells expressing IgDR to treat RA. The expression levels of Wnt5A and Frizzled 5 are higher in RA synovial tissue specimens. The complex of Wnt5A-Fzd5-LRP5/6-CTHRC1 promotes the expression of hypoxia inducible factor-1α by activating nuclear factor kappa-B (NF-κB), leading to high expression of VEGF and participating in angiogenesis. VEGF is the strongest angiogenic factor found so far. Here, we aimed to explore whether IgD participates in synovitis by binding to IgDR and regulating the activation of Wnt5A-Fzd5-CTHRC1-NF-κB signaling pathway in fibroblast synovial cells (FLSs), whether IgD-Fc-Ig fusion protein inhibits VEGF production in FLS of CIA and explore mechanism. We found that IgDR is expressed on MH7A and FLS. IgD promotes VEGF expression by activating Wnt5A-Fzd5-CTHRC1-NF-κB signaling pathway in MH7A and FLS. After activation of Fzd5 with Wnt5A, IgD-Fc-Ig reduced VEGF-A level in the culture supernatant of MH7A stimulation by IgD. The expressions of CTHRC1, Fzd5, p-P65 and VEGF in MH7A and FLSs were down-regulated after IgD-Fc-Ig treatment. IgD-Fc-Ig suppressed the combination of CTHRC1 and Fzd5 as well. By using the animal model, we demonstrated that IgD-Fc-Ig suppress ankle CTHRC1 and Fzd5 production resulted in inhibition of index of joint inflammation of CIA rats, which were consistent with vitro results. Conclusively, IgD-Fc-Ig inhibits IgD and Wnt5A-induced angiogenesis and joint inflammation by suppressing the combination of CTHRC1 and Fzd5. Our results show that IgD-Fc-Ig exerts its suppressive effect on IgD and Wnt5A by Wnt5A-Fzd5-CTHRC1-NF-κB signaling pathway.

Critical roles of the E3 ubiquitin ligase FBW7 in B-cell response and the pathogenesis of experimental autoimmune arthritis.

Proper regulation of B-cell function is essential for effective humoral immunity and maintenance of immune tolerance. Here, we found that FBW7 (F-box/WD40 repeat-containing protein 7) is highly expressed in germinal centre B and B1 cells, and confirmed that it has an intrinsic role in maintaining homeostasis of mature B cells and B-1 cells. FBW7 deletion led to an impairment of antibody response, and although germinal centre formation was not affected, antibody class-switch recombination and affinity maturation processes were defective. Likewise, memory immune response was severely impaired. Moreover, FBW7 ablation ameliorated the pathogenesis of an autoimmune disease model, collagen-induced arthritis, by reducing the production of anti-collagen II autoantibodies. Taken together, these data suggest that FBW7 may be an attractive target for developing new therapeutics for the treatment of autoimmune diseases.

Atelocollagen-Embedded Chondrocyte Precursors as a Treatment for Grade-4 Cartilage Defects of the Femoral Condyle: A Case Series with up to 9-Year Follow-Up.

We demonstrated the safety and efficacy of autologous chondrocyte precursor (CP) cell therapy in repairing Grade 4 cartilage defects of medial femoral condyles. The autologous bone marrow mesenchymal stem cells of each participant were isolated, amplified, and then differentiated into CPs in atelocollagen. Neotissues made of CPs were implanted into cartilage defects with an average cell density of 4.9 ± 2.1 × 106 cells/cm2 through arthrotomy. The knee function was evaluated with the International Knee Documentation Committee (IKDC) subjective knee form. Patients' knee functions significantly improved by the 28th week (IKDC score = 68.3 ± 12.1), relative to the initial functionality before the CP therapy (IKDC score = 46.1 ± 16.4, p-value = 0.0014). Nine of these twelve patients maintained good knee functions for 9 years post-implantation (IKDC score = 69.8 ± 12.3) at levels higher than the pre-implantation values (p-value = 0.0018). Patients were evaluated with MRI and arthroscopy, and the defective sites exhibited a smooth surface without a gap between the implant and host tissue. This study demonstrates that autologous CPs successfully engraft into the host tissue and result in the re-formation of hyaline-like cartilage, thereby improving the impaired knee functions. Most importantly, no adverse event was reported during this long-term follow-up period.

Efficacy of dental pulp-derived stem cells conditioned medium loaded in collagen hydrogel in spinal cord injury in rats: Stereological evidence.

Spinal cord injury (SCI) causes histological alterations which in turn affects functional activity. Studies have demonstrated that dental pulp-derived stem cells conditioned medium has beneficial effects on the nervous system. Besides, collagen hydrogel acts as a drug releasing system in SCI investigations. This research aimed to evaluate effects of dental pulp-derived stem cells conditioned medium loaded in collagen hydrogel in SCI. After culturing of Stem cells from human exfoliated deciduous teeth (SHEDs), SHED-conditioned medium (SHED-CM) was harvested and concentrated. Collagen hydrogel containing SHED-CM was prepared. The rats were divided into five groups receiving laminectomy, compressive SCI with or without intraspinal injection of biomaterials (SHED-CM and collagen hydrogel with or without SHED-CM). After 6 weeks, histological parameters were estimated using stereological methods. The total volume of preserved white matter and gray matter (p < 0.05) as well as the total number of neurons and oligodendrocytes in the rats received SHED-CM loaded in collagen hydrogel were significantly higher, and also lesion volume and lesion length were significantly lower (p < 0.05) compared to those of the other injured groups. In conclusion, intraspinal administration of SHED-CM loaded in collagen hydrogel leads to neuroprotection, proposing a cell-free therapeutic approach in SCI.

Monitoring urinary collagen metabolite changes following collagen peptide ingestion and physical activity using ELISA with anti active collagen oligopeptide antibody.

Active collagen oligopeptides (ACOP) are bioactive collagen-derived peptides detected by a recently-established ELISA. To facilitate studies of the function and metabolism of these products, this study aims to determine which of these peptides is recognized by a novel anti-ACOP antibody used in this ELISA. We then investigate the effect of collagen peptide (CP) ingestion and exercise on urinary ACOP concentrations in a cohort of university student athletes using colorimetric, LC-MS/MS, and ELISA. We observed that the antibody showed strong cross-reactivity to Pro-Hyp and Gly-Pro-Hyp and weak cross-reactivity to commercial CP. CP ingestion increased the urinary level of ACOP over time, which correlated highly with urinary levels of peptide forms of Hyp and Pro-Hyp. Physical activity significantly decreased the urinary ACOP level. This study demonstrates changes in urinary ACOP following oral CP intake and physical activity using ELISA with the novel anti-ACOP antibody. Thus, ACOP may be useful as a new biomarker for collagen metabolism.

Genome Edited Sirt1-Overexpressing Human Mesenchymal Stem Cells Exhibit Therapeutic Effects in Treating Collagen-Induced Arthritis.

Even though mesenchymal stem cells (MSCs) are known for cartilage regeneration, their therapeutic efficacy needs to be enhanced. In the present study, we produced genome-edited silent information regulator 2 type 1 (Sirt1)-overexpressing MSCs, and evaluated their therapeutic potential in a damaged cartilage mouse liver fibrosis model. The Sirt1 gene was successfully inserted into a 'safe harbor' genomic locus in amniotic mesenchymal stem cells (AMMs), and the chondrogenic properties of the Sirt1 gene overexpressing AMMs (AMM/S) were characterized using quantitative PCR and histology. Therapeutic potentials were investigated in a collagen-induced arthritis (CIA) mouse model. Chondrocyte-differentiated AMM/S expressed cartilage-specific genes and were positive for Safranin O staining. Transplantation of AMM/S attenuated CIA progression and suppressed T helper (Th)-17 cell activation while increasing the Treg cell population in CIA mice. Pro-inflammatory factors, such as interleukin (IL)-1ß, IL-6, monocyte chemoattractant protein (MCP)-1, and tumor necrosis factor (TNF)-α were significantly decreased in AMM/S-injected joint tissues. In conclusion, genome-edited AMM/S may represent a safe and alternative therapeutic option for the treatment and repair of damaged cartilage, or in inflammatory joint arthritis.