Chondrocyte Adipogenic Differentiation in Softening Osteoarthritic Cartilage

A chondrocyte-to-osteoblast lineage continuum exists in the growth plate. Adipogenic differentiation of chondrocytes in vivo should be investigated. Here, unilateral anterior crossbite (UAC), which can induce osteoarthritic lesions in the temporomandibular joint (TMJ), was applied to 6-wk-old C57BL/6 mice. Matrix loss in TMJ cartilage was obvious, as demonstrated by safranin O staining, and the condylar cartilage elastic modulus values, detected by using atomic force microscopy (AFM), were reduced, indicating cartilage softening that might be linked with loss of the highly charged proteoglycan. By crossing the Rosa26/tdTomato (TdT) mice with Sox9;CreERT2 mice or with Col10;CreERT2 mice, we obtained the Sox9-TdT and Col10-TdT strains, respectively, in which the Sox9- or Col10-expressing cells, accordingly, were labeled by TdT. A few TdT-labeled cells in both strains expressed AdipoQ or DMP-1. The Sox9-TdT+AdipoQ+ cells were primarily located in the deep zone cartilage and then in the whole cartilage. Col10-TdT+AdipoQ+ cells, Sox9-TdT+DMP-1+ cells, and Col10-TdT+DMP-1+ cells were located in the deep zone region. UAC promoted AdipoQ and DMP-1 expression in cartilage. The percentages of Sox9-TdT+AdipoQ+ and Col10-TdT+AdipoQ+ cells to Sox9-TdT+ and Col10-TdT+ cells, respectively, were increased (both P < 0.05), implying that more chondrocytes were undergoing adipogenic differentiation in the UAC group, the cartilage of which was softened. The percentages of Sox9-TdT+DMP-1+ and Col10-TdT+DMP-1+ cells to Sox9-TdT+ cells and Col10-TdT+ cells, respectively, were increased (both P < 0.05), consistent with our report that UAC enhanced deep zone cartilage calcification, causing stiffening of the deep zone cartilage. Our present data demonstrated that TMJ chondrocyte descendants can become adipogenic in vivo in addition to becoming osteogenic. This potential was promoted in osteoarthritic cartilage, in which deep zone cartilage calcification-associated cartilage stiffening and proteoglycan loss-associated cartilage softening were both stimulated.

Therapeutic Strategies for IVD Regeneration through Hyaluronan/SDF-1-Based Hydrogel and Intravenous Administration of MSCs

Intervertebral disc (IVD) degeneration involves a complex cascade of events, including degradation of the native extracellular matrix, loss of water content, and decreased cell numbers. Cell recruitment strategies for the IVD have been increasingly explored, aiming to recruit either endogenous or transplanted cells. This study evaluates the IVD therapeutic potential of a chemoattractant delivery system (HAPSDF5) that combines a hyaluronan-based thermoreversible hydrogel (HAP) and the chemokine stromal cell derived factor-1 (SDF-1). HAPSDF5 was injected into the IVD and was combined with an intravenous injection of mesenchymal stem/stromal cells (MSCs) in a pre-clinical in vivo IVD lesion model. The local and systemic effects were evaluated two weeks after treatment. The hydrogel by itself (HAP) did not elicit any adverse effect, showing potential to be administrated by intradiscal injection. HAPSDF5 induced higher cell numbers, but no evidence of IVD regeneration was observed. MSCs systemic injection seemed to exert a role in IVD regeneration to some extent through a paracrine effect, but no synergies were observed when HAPSDF5 was combined with MSCs. Overall, this study shows that although the injection of chemoattractant hydrogels and MSC recruitment are feasible approaches for IVD, IVD regeneration using this strategy needs to be further explored before successful clinical translation.

S-Equol Protects Chondrocytes against Sodium Nitroprusside-Caused Matrix Loss and Apoptosis through Activating PI3K/Akt Pathway

Osteoarthritis (OA) is a common chronic disease with increasing prevalence in societies with more aging populations, therefore, it is causing more concern. S-Equol, a kind of isoflavones, was reported to be bioavailable and beneficial to humans in many aspects, such as improving menopausal symptoms, osteoporosis and prevention of cardiovascular disease. This study investigated the effects of S-Equol on OA progress in which rat primary chondrocytes were treated with sodium nitroprusside (SNP) to mimic OA progress with or without the co-addition of S-Equol for the evaluation of S-Equol’s efficacy on OA. Results showed treatment of 0.8 mM SNP caused cell death, and increased oxidative stress (NO and H2O2), apoptosis, and proteoglycan loss. Furthermore, the expressions of MMPs of MMP-2, MMP-3, MMP-9, and MMP-13 and p53 were increased. The addition of 30 μM S-Equol could lessen those caused by SNP. Moreover, S-Equol activates the PI3K/Akt pathway, which is an upstream regulation of p53 and NO production and is associated with apoptosis and matrix degradation. As a pretreatment of phosphoinositide 3-kinases (PI3K) inhibitor, all S-Equol protective functions against SNP decrease or disappear. In conclusion, through PI3K/Akt activation, S-Equol can protect chondrocytes against SNP-induced matrix degradation and apoptosis, which are commonly found in OA, suggesting S-Equol is a potential for OA prevention.

Reconstruction for Defects of Total Nail Bed and Germinal Matrix Loss with Acellular Dermal Matrix Coverage and Subsequently Skin Graft

Background and Objectives: Nail bed and germinal matrix loss due to wide excision for fingertip tumors or malignancy are occasionally encountered complications. These defects also result from severely comminuted fingertip crush injuries. Large-area dorsal finger or toenail bed defects, which usually present with phalangeal bone exposure, remain challenging regardless of the usage of different reconstruction strategies. This study aimed to evaluate the clinical outcome of a staged operation with an acellular dermal matrix coverage and subsequent skin graft as reconstruction for defects of total nail bed, germinal matrix loss, and bone exposure. Materials and Methods: From April 2018 to October 2019, four patients with total nail bed, germinal matrix, and bone exposure loss after surgery were enrolled in our series. A staged operation of the acellular dermal matrix coverage with subsequent skin graft was performed on these patients. Skin graft take rate, oncological prognosis, and cosmetic outcome were evaluated. Patients were followed up for 5–13 months. An excellent skin graft take rate with a satisfying aesthetic result without local malignancy recurrence was noted. Minimal functional deficit and donor site morbidity were reported. Results: A staged operation with acellular dermal matrix coverage and subsequent skin graft proves to serve as a feasible strategy for patients who experience total nail bed, germinal matrix loss, and bone exposure after surgery. Conclusions: This reconstruction method provides a reliable repair result, satisfying aesthetic outcomes, as well as having minimal functional deficits and donor site morbidity.

Estrogen Selectively Enhances TMJ Disc but Not Knee Meniscus Matrix Loss

The preponderance of temporomandibular joint (TMJ) degenerative disorders in women and their early onset during reproductive years have implicated female sex hormones, particularly 17-β estradiol (E2), in the pathogenesis of these disorders. Nevertheless, the mechanisms by which E2 contributes to TMJ degenerative disorders and the reasons for its targeted effects on the TMJ but not other joints remain poorly understood. Here, we developed an ovariectomized mouse model in which systemic E2 concentrations mimicked those in cycling women, and we determined the effect of E2 on the targeted turnover of TMJ fibrocartilage matrix via E2-induced matrix metalloproteinases MMP9 and MMP13. Infusion of E2 and progesterone (P4; hormone control) over 7 d resulted in 5- and 8-fold greater serum E2 and P4 levels relative to controls, respectively, achieving systemic hormone levels similar to high baseline levels in cycling women. Administration of E2 but not P4 caused a significant loss of TMJ collagen and glycosaminoglycans, which was accompanied by amplification of ERα and specific increases in MMP9 and MMP13 expression. This dose of E2 had no effect on knee meniscus fibrocartilage, demonstrating the specificity of the degradative effect of E2. Dose-response experiments showed a greater sensitivity and a higher peak induction of MMP9 and MMP13 in TMJ fibrocartilaginous cells than knee meniscus cells to E2, providing an explanation for the differential responses of these tissues to E2. Using MMP9- and MMP13-null mice, we observed no discernible effects of each proteinase individually to E2-mediated TMJ matrix loss but noted a significant compensatory reciprocal induction of each MMP by E2 in the absence of the other. The redundancy in E2’s induction of MMP9 and MMP13 suggests that the proteinases may together contribute to E2-mediated TMJ fibrocartilage loss. These results advance our understanding of E2-mediated upregulation of MMP9 and MMP13 on fibrocartilage matrix turnover targeted to the TMJ.

Bioregulatory drugs in osteoarthritis management

Osteoarthritis (OA) is a degenerative joint disease. Modern theories consider various structural (cartilage destruction) and biophysical disorders (matrix loss of glycosaminoglycans) as the basis of acute and chronic pain syndrome. The main aim of OA therapy is pain relief and functional improvement. To manage pain syndrome in OA it is reasonable to use complex bioregulatory drugs (CBD) (Traumeel S, Zeel T, Discus compositum) both in monotherapy and in combined treatment. The effectiveness of CBD is comparable to that of NSAIDs and CS.

Long-Term Human Motion Prediction by Modeling Motion Context and Enhancing Motion Dynamics

Human motion prediction aims at generating future frames of human motion based on an observed sequence of skeletons. Recent methods employ the latest hidden states of a recurrent neural network (RNN) to encode the historical skeletons, which can only address short-term prediction. In this work, we propose a motion context modeling by summarizing the historical human motion with respect to the current prediction. A modified highway unit (MHU) is proposed for efficiently eliminating motionless joints and estimating next pose given the motion context. Furthermore, we enhance the motion dynamic by minimizing the gram matrix loss for long-term motion prediction. Experimental results show that the proposed model can promisingly forecast the human future movements, which yields superior performances over related state-of-the-art approaches. Moreover, specifying the motion context with the activity labels enables our model to perform human motion transfer.