Fibrocartilage

Aging is a pivotal risk factor for intervertebral disc degeneration (IVDD) and chronic low back pain (LBP). The restoration of aging nucleus pulposus cells (NPCs) to a youthful epigenetic state is crucial for IVDD treatment, but remains a formidable challenge. Here, we proposed a strategy to partially reprogram and reinstate youthful epigenetics of senescent NPCs by delivering a plasmid carrier that expressed pluripotency-associated genes (Oct4, Klf4 and Sox2) in Cavin2-modified exosomes (OKS@M-Exo) for treatment of IVDD and alleviating LBP. The functional OKS@M-Exo efficaciously alleviated senescence markers (p16INK4a, p21CIP1 and p53), reduced DNA damage and H4K20me3 expression, as well as restored proliferation ability and metabolic balance in senescent NPCs, as validated through in vitro experiments. In a rat model of IVDD, OKS@M-Exo maintained intervertebral disc height, nucleus pulposus hydration and tissue structure, effectively ameliorated IVDD via decreasing the senescence markers. Additionally, OKS@M-Exo reduced nociceptive behavior and downregulated nociception markers, indicating its efficiency in alleviating LBP. The transcriptome sequencing analysis also demonstrated that OKS@M-Exo could decrease the expression of age-related pathways and restore cell proliferation. Collectively, reprogramming by the OKS@M-Exo to restore youthful epigenetics of senescent NPCs may hold promise as a therapeutic platform to treat IVDD.

Low back pain (LBP) caused by nucleus pulposus degeneration and calcification leads to great economic and social burden worldwide. Unexpectedly, no previous studies have demonstrated the association and the underlying mechanism between nucleus pulposus tissue degeneration and calcification formation. Secreted Phosphoprotein 1 (SPP1) exerts crucial functions in bone matrix mineralization and calcium deposition. Here, a novel function of SPP1 is reported, namely that it can aggravate nucleus pulposus cells (NPs) degeneration by negatively regulating extracellular matrix homeostasis. The degenerated NPs have a higher mineralization potential, which is achieved by SPP1. Mechanistically, SPP1 can accelerate the degeneration of nucleus pulposus cells by activating integrin α5β1 (ITGα5/β1), aggravating mitochondrial damage and inhibiting mitophagy. SPP1-ITGα5/β1 axis inhibits mitophagy by PINK1/PARKIN pathway blockade. In conclusion, SPP1 activates ITGα5/β1 to inhibit mitophagy, accelerates NPs degeneration, and induces calcification, thereby leading to intervertebral disc degeneration (IVDD) and calcification, identifying the potentially unknown mechanism and relationship between IVDD and calcification. Important insights are provided into the role of SPP1 in nucleus pulposus calcification in IVDD by inducing nucleus pulposus cell senescence through inhibition of mitophagy and may help develop potential new strategies for IVDD treatment.

PurposeThe aim of part one of this EU-US consensus was to combine literature research and expertise to provide recommendations for the usage of rehabilitation (including physical therapy) of patients undergoing surgical treatment for degenerative meniscus lesions or acute meniscus tears (including meniscectomy, repair, or reconstruction). Prevention programmes, non-operative treatment of acute tears and degenerative lesions, return to sports and patient-reported outcome measures will be presented in a part II article.MethodsThis consensus followed the European Society for Sports Traumatology and Arthroscopy (ESSKA)'s 'formal consensus' methodology. For this combined ESSKA, American Orthopedic Society for Sports Medicine and American Academy of Sports Physical Therapy initiative, 67 experts (26 in the steering group and 41 in the rating group) from 14 countries (US and 13 European countries), including orthopaedic surgeons, sports medicine doctors and physiotherapists were involved. Steering group members established guiding questions, searched the literature and proposed statements. Rating group members assessed the statements according to a Likert scale and provided grades of recommendations, reaching a final agreement about rehabilitation of the knee after meniscus surgery. Final documents were then assessed by a peer review group to address the geographical adaptability.ResultsThe overall level of evidence in the literature was low. Of the 19 questions (leading to 29 statements), 1 received a Grade A of recommendation, 2 a Grade B, 9 a Grade C and 17 a Grade D. Nevertheless, the mean median rating of all questions was 8.2/9 (9 being the highest rating on a scale of 1-9). The global mean rating was 8.4 ± 0.2, indicating a high agreement. Rehabilitation depends on the type of lesion, the treatment performed and is the same after medial or lateral meniscus surgery. Rehabilitation after meniscectomy should follow a criterion-based rehabilitation protocol, based on milestones rather than a time-based protocol. After meniscus repair and reconstruction, rehabilitation should be progressed according to both time and criterion-based milestones.ConclusionRehabilitation after meniscus surgery is a debated topic that may influence surgical outcomes if not optimally performed. This international formal consensus established clear, updated and structured recommendations for both surgeons and physiotherapists treating patients after meniscus surgery.Level of evidenceLevel I, consensus.

Intervertebral disc degeneration (IVDD) is driven by persistent inflammation-oxidative stress that disrupts annulus fibrosus (AF) homeostasis. Guided by network pharmacology and docking, we prioritized the NF-κB-LCN2 axis as a druggable target of wedelolactone (WDL). To achieve targeted modulation, we engineered a dual-network ROS-responsive hydrogel (WPG) in which a phenylboronic-ester/PVA redox-cleavable network interpenetrates a covalently crosslinked GelMA-elastin matrix, enabling mechanically robust yet stimulus-triggered WDL release. WDL suppressed NF-κB activation and downregulated LCN2 in both macrophages and AF cells. Conditioned-medium co-culture demonstrated that WDL disrupts macrophage-derived LCN2-mediated paracrine amplification, breaking the self-sustaining inflammatory loop. Bulk RNA-seq across both cell types revealed coordinated downregulation of NF-κB - driven chemokine cascades and restoration of adhesion and ECM gene programs following WPG treatment. In a rat AF-defect model, intradiscal WPG administration preserved disc height and T2-weighted MRI signal, reduced MMP13 while increasing Collagen I and Aggrecan expression, suppressed nuclear P-p65 and LCN2, and improved segment biomechanics-without eliciting adverse hematological or organ responses. Collectively, these findings establish that aligning molecular targeting (NF-κB-LCN2 modulation) with the pathophysiological context via ROS-gated delivery provides a synergistic strategy for AF repair and attenuation of IVDD progression.