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Type II collagen is the major cartilage matrix protein in the jawed vertebrate skeleton. Lampreys and hagfishes, by contrast, are thought to have noncollagenous cartilage. This difference in skeletal structure has led to the hypothesis that the vertebrate common ancestor had a noncollagenous skeleton, with type II collagen becoming the predominant cartilage matrix protein after the divergence of jawless fish from the jawed vertebrates ≈500 million years ago. Here we report that lampreys have two type II collagen (Col2α1) genes that are expressed during development of the cartilaginous skeleton. We also demonstrate that the adult lamprey skeleton is rich in Col2α1 protein. Furthermore, we have isolated a lamprey orthologue of Sox9, a direct transcriptional regulator of Col2α1 in jawed vertebrates, and show that it is coexpressed with both Col2α1 genes during skeletal development. These results reveal that the genetic pathway for chondrogenesis in lampreys and gnathostomes is conserved through the activation of cartilage matrix molecules and suggest that a collagenous skeleton evolved surprisingly early in vertebrate evolution.

Collagen supplements have gained significant market popularity, with numerous products claiming to improve knee osteoarthritis symptoms. Previous clinical studies have primarily evaluated individual collagen formulations, with most being industry-sponsored, which raises potential bias concerns. This study aimed to evaluate the efficacy of combined undenatured type II collagen (UC-II) and hydrolysed collagen supplementation in patients with knee osteoarthritis. In this randomised, double-blind, placebo-controlled trial, 68 patients with knee osteoarthritis were divided into two groups: one receiving collagen supplements (tablets containing hydrolysed collagen and UC-II) and the other receiving a placebo. Clinical outcomes, including pain intensity (Verbal Numerical Rating Scale), functional outcomes (Knee Injury and Osteoarthritis Outcome Score [KOOS]), rescue medication consumption, and patient satisfaction, were assessed at baseline, 2, 6, and 12 weeks. Baseline demographic characteristics were comparable between the collagen and placebo groups. Both groups showed significant improvements in pain intensity ( p  < 0.001) and KOOS scores over time. However, no significant differences were observed between the groups in terms of pain intensity, functional outcomes, rescue medication consumption, or patient satisfaction ( p  > 0.05). No adverse effects were reported in either group. Combined UC-II and hydrolysed collagen supplementation over 12 weeks did not demonstrate superior efficacy compared with that of the placebo in managing knee osteoarthritis symptoms. Further research is required to explore the potential long-term benefits of combined collagen supplementation. Clinical Trial Registration : ClinicalTrials.gov (NCT06229951): registered on January 16, 2024.

Articular cartilage is a connective tissue consisting of a specialized extracellular matrix （ECM） that dominates the bulk of its wet and dry weight. Type Ⅱ collagen and aggrecan are the main ECM proteins in cartilage. However, little attention has been paid to less abundant molecular components, especially minor collagens, including type Ⅳ, Ⅵ, Ⅸ, Ⅹ, Ⅺ, Ⅻ, ⅩⅢ, and ⅩⅣ, etc. Although accounting for only a small fraction of the mature matrix, these minor collagens not only play essential structural roles in the mechanical properties, organization, and shape of articular cartilage, but also fulfil specific biological functions. Genetic studies of these minor collagens have revealed that they are associated with multiple connective tissue diseases, especially degenerative joint disease. The progressive destruction of cartilage involves the degradation of matrix constituents including these minor collagens. The generation and release of fragmented molecules could generate novel biochemical markers with the capacity to monitor disease progression, facilitate drug development and add to the existing toolbox for in vitro studies, preclinical research and clinical trials.

Numerous studies have shown that type II collagen (CII) has a potential role in the treatment of rheumatoid arthritis. However, most of the current studies have used terrestrial animal cartilage as a source of CII extraction, with fewer studies involving marine organisms. Based on this background, collagen (BSCII) was isolated from blue shark (Prionace glauca) cartilage by pepsin hydrolysis and its biochemical properties including protein pattern, total sugar content, microstructure, amino acid composition, spectral characteristics and thermal stability were further investigated in the present study. The SDS-PAGE results confirmed the typical characteristic of CII, comprising three identical α1 chains and its dimeric β chain. BSCII had the fibrous microstructure typical of collagen and an amino acid composition represented by high glycine content. BSCII had the typical UV and FTIR spectral characteristics of collagen. Further analysis revealed that BSCII had a high purity, while its secondary structure comprised 26.98% of β-sheet, 35.60% of β-turn, 37.41% of the random coil and no α-helix. CD spectra showed the triple helical structure of BSCII. The total sugar content, denaturation temperature and melting temperature of BSCII were (4.20 ± 0.03)%, 42 °C and 49 °C, respectively. SEM and AFM images confirmed a fibrillar and porous structure of collagen and denser fibrous bundles formed at higher concentrations. Overall, CII was successfully extracted from blue shark cartilage in the present study, and its molecular structure was intact. Therefore, blue shark cartilage could serve as a potential source for CII extraction with applications in biomedicine.

Recombinant collagen production, especially using yeasts as expression systems, could represent a promising alternative over traditional extractive methods from animal sources, offering controllable, scalable, and high-quality products. Monitoring the efficiency and efficacy of procollagen/collagen expression, especially in the initial fermentation phases, can be difficult and time consuming, as biological matrices necessitate purification and commonly used analytical methods are only partially informative. We propose a straightforward, efficient, and reusable immunocapture system able to specifically isolate human procollagen type II from fermentation broths and to release it in few experimental steps. A recovered sample allows for a detailed characterization providing information on structural identity and integrity, which can strongly support the monitoring of fermentation processes. The immunocapture system relies on the use of protein A–coated magnetic beads which have been functionalized and cross-linked with a human anti-procollagen II antibody (average immobilization yield of 97.7%) to create a stable and reusable support for the specific procollagen fishing. We set up the binding and release conditions ensuring specific and reproducible binding with a synthetic procollagen antigen. The absence of non-specific interaction with the support and binding specificity was demonstrated, and the latter was also confirmed by a peptide mapping epitope study in reversed-phase liquid chromatography high-resolution mass spectrometry (RP-LC-HRMS). The bio-activated support proved to be reusable and stable over 21 days from the initial use. Finally, the system was successfully tested on a raw yeast fermentation sample to provide a proof of concept of the applicability within recombinant collagen production. Graphical Abstract

From early dinosaurs with as many as nine wrist bones, modern birds evolved to develop only four ossifications. Their identity is uncertain, with different labels used in palaeontology and developmental biology. We examined embryos of several species and studied chicken embryos in detail through a new technique allowing whole-mount immunofluorescence of the embryonic cartilaginous skeleton. Beyond previous controversy, we establish that the proximal-anterior ossification develops from a composite radiale+intermedium cartilage, consistent with fusion of radiale and intermedium observed in some theropod dinosaurs. Despite previous claims that the development of the distal-anterior ossification does not support the dinosaur-bird link, we found its embryonic precursor shows two distinct regions of both collagen type II and collagen type IX expression, resembling the composite semilunate bone of bird-like dinosaurs (distal carpal 1+distal carpal 2). The distal-posterior ossification develops from a cartilage referred to as \"element x,\" but its position corresponds to distal carpal 3. The proximal-posterior ossification is perhaps most controversial: It is labelled as the ulnare in palaeontology, but we confirm the embryonic ulnare is lost during development. Re-examination of the fossil evidence reveals the ulnare was actually absent in bird-like dinosaurs. We confirm the proximal-posterior bone is a pisiform in terms of embryonic position and its development as a sesamoid associated to a tendon. However, the pisiform is absent in bird-like dinosaurs, which are known from several articulated specimens. The combined data provide compelling evidence of a remarkable evolutionary reversal: A large, ossified pisiform re-evolved in the lineage leading to birds, after a period in which it was either absent, nonossified, or very small, consistently escaping fossil preservation. The bird wrist provides a modern example of how developmental and paleontological data illuminate each other. Based on all available data, we introduce a new nomenclature for bird wrist ossifications.

The aim of this study was to examine the influence of matrix elasticity on the maintenance of the chondrogenic phenotype of chondrocytes cultured in monolayer. We used a two-dimensional culturing system in which polyacrylamide gels with different concentrations of bis-acrylamide were coated with collagen type I. Matrices with a Young's modulus of 4, 10, 40, and 100 kPa were produced, as determined by atomic force microscopy. Porcine chondrocytes were cultivated on these matrices at a low density for 7 days. The proliferation of cells was analyzed by 5-Bromo-2′-deoxy-uridine incorporation. Maintenance of the chondrogenic phenotype was analyzed by measuring collagen type I, type II, and aggrecan gene expression, immunofluorescence staining for collagen type II, and phalloidin staining for actin filaments. Cellular proliferation and actin organization were decreased on matrices of 4 kPa compared with stiffer substrates. The differentiated phenotype of the chondrocytes grown on matrices of 4 kPa was stabilized, indicated by higher collagen type II and aggrecan, and lower collagen type I expression. These findings indicate that chondrocytes sense the elasticity of the matrix and might be used for the design of scaffolds with mechanical properties specifically tailored to support the chondrogenic phenotype in tissue engineering applications.

Cartilage lesions and osteoarthritis (OA) presents an ever-increasing clinical and socioeconomic burden. Synovial inflammation and articular inflammatory environment are the key factor for chondrocytes apoptosis and hypertrophy, ectopic bone formation and OA progression. To effectively treat OA, it is critical to develop a drug that skews inflammation toward a pro-chondrogenic microenvironment. In this narrative and critical review, we aim to see the potential use of immune cells modulation or cell therapy as therapeutic alternatives to OA patients. Macrophages are immune cells that are present in synovial lining, with different roles depending on their subtypes. These cells can polarize to pro-inflammatory (M1) and anti-inflammatory (M2) phenotypes, being the latter associated with wound-healing by the production of ARG-1 and pro-chondrogenic cytokines, such as IL-10, IL-1RA, and TGF-b. Emerging evidence reveals that macrophage shift can be determined by several stimuli, apart from the conventional IL-4, IL-13, and IL-10. Evidences show the potential of physical exercise to induce type 2 response, favoring M2 polarization. Moreover, macrophages in contact with oxLDL have effect on the production of anabolic mediators as TGF-b. In the same direction, type II collagen, that plays a critical role in development and maturation process of chondrocytes, can also induce M2 macrophages, increasing TGF-b. The mTOR pathway activation in macrophages was shown to be able to polarize macrophages , though further studies are required. The possibility to use mesenchymal stem cells (MSCs) in cartilage restoration have a more concrete literature, besides, MSCs also have the capability to induce M2 macrophages. In the other direction, M1 polarized macrophages inhibit the proliferation and viability of MSCs and impair their ability to immunosuppress the environment, preventing cartilage repair. Therefore, even though MSCs therapeutic researches advances, other sources of M2 polarization are attractive issues, and further studies will contribute to the possibility to manipulate this polarization and to use it as a therapeutic approach in OA patients.

A lack of current methods for major histocompatibility class II epitope identification prompted Isamu Hartman and his colleagues to develop a cell-free system that they used to identify physiologically selected immunodominant epitopes of model antigens, as well as for de novo epitope identification. Immunodominance is defined as restricted responsiveness of T cells to a few selected epitopes from complex antigens. Strategies currently used for elucidating CD4 + T cell epitopes are inadequate. To understand the mechanism of epitope selection for helper T cells, we established a cell-free antigen processing system composed of defined proteins: human leukocyte antigen-DR1 (HLA-DR1), HLA-DM and cathepsins. Our reductionist system successfully identified the physiologically selected immunodominant epitopes of two model antigens: hemagglutinin-1 (HA1) from influenza virus (A/Texas/1/77) and type II collagen (CII). When applied for identification of new epitopes from a recombinant liver-stage antigen of malaria falciparum (LSA-NRC) or HA1 from H5N1 influenza virus ('avian flu'), the system selected single epitopes from each protein that were confirmed to be immunodominant by their capacity to activate CD4 + T cells from H5N1-immunized HLA-DR1–transgenic mice and LSA-NRC–vaccinated HLA-DR1–positive human volunteers. Thus, we provide a new tool for the identification of physiologically relevant helper T cell epitopes from antigens.

Objective. To analyze the effects of modified Duhuo Jisheng Decoction combined with arthroscopic surgery on bone metabolism, oxidative stress, and serum TLR4 and TGF-β1 in patients with knee osteoarthritis (KOA). Methods. Prospectively select 82 patients with KOA from January 2020 to January 2022 in our hospital and divide them into the control group and observation group according to the random number table method, with 41 patients in each group. The control group was treated with arthroscopic surgery alone and routine anti-infection after operation. The observation group was treated with Duhuo Jisheng Decoction on the basis of the treatment of the control group. The patients in the two groups were treated continuously for 4 weeks. The improvement of patients’ symptoms was evaluated by the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Before treatment and 4 weeks after treatment, the scores of traditional Chinese medicine (TCM) symptoms, bone metabolism indicators (cartilage oligomeric matrix protein (COMP), collagen type II carboxy terminal peptide (ctx-II), and matrix metalloproteinase-3 (MMP-3)), oxidative stress indicators (superoxide dismutase (SOD), glutathione peroxidase (GSHPx), malondialdehyde (MDA), nitric oxide (NO)), serum Toll-like receptor 4 (TLR4), and transforming growth factor β (TGF-β) level were compared between the two groups. Results. After treatment, the WOMAC score of the two groups decreased (42.45±10.83) in the observation group and (67.81±14.63) in the control group. The WOMAC score of the observation group was lower than that of the control group (P<0.05). After treatment, the levels of COMP, CTX-II, and MMP-3 in the two groups decreased, and the levels of COMP, CTX-II, and MMP-3 in the observation group were lower than those in the control group (P<0.05). After treatment, the levels of SOD and GSHPx increased, while the levels of MDA and NO decreased in the two groups. The levels of SOD and GSHPx in the observation group were higher than those in the control group, while the levels of MDA and NO were lower than those in the control group (P<0.05). After treatment, the TLR4 level in the observation group was lower than that of the control group, and the level of TGF-β in the observation group was higher than that of the control group (P<0.05). Conclusion. Compared with arthroscopic surgery alone, combined with modified Duhuo Jisheng Decoction can better alleviate the clinical symptoms of patients with KOA, improve their bone metabolism, oxidative stress indicators, and serum TLR4 and TGF-β 1 level, and reduce the inflammatory injury of knee joint.