Aging and musculoskeletal health

Musculoskeletal health is crucial for people's mobility and ability to live independently. The prevalence of musculoskeletal disorders increases with age, and an impaired musculoskeletal system affects both the quality and length of life. Osteoporosis, osteoarthritis (OA), and intervertebral discs degeneration (IDD) are major health burdens in the aging population. In this issue, Wu et al. analyzed global, regional, and national trends of femur fractures using data from the Global Burden of Disease Study 2019 and machine learning algorithms [1]. They found that both age-standardized prevalence rate (ASPR) and age-standardized incidence rate (ASIR) were higher in women than men in the >75-year group, however, years living with disability (YLDs) were lower in women than men in the >60-year group. They predicted that global femur fracture ASIR might decline between 2020 and 2030 while ASPR and YLDs could rise. These findings suggest more efforts are needed to reduce disability rates associated with femur fractures among elderly individuals.

To find new therapies on osteoporosis, Shen et al. examined the impact of L-arginine on bone homeostasis in aged and ovariectomized mouse models [2]. They discovered that L-arginine mitigated bone loss and promoted osteogenesis and angiogenesis by regulating the expression of PINK1/Parkin and Bnip3 in osteoblast-lineage and endothelial cells' mitochondria. In another study, Liu et al. explored the mechanisms behind age-related mandibular osteoporosis and investigated the effects of metformin on mandibular osteopenia in Bmi1−/− mice [3]. It was observed that Bmi1 loss induced cellular senescence in jaw tissue, leading to reduced mandible bone density through the AMPK/mTOR signaling pathway. Administration of metformin normalized AMPK-mTOR balance and significantly improved mandibular bone architecture in Bmi1−/− mice. These findings demonstrate that supplementation with either L-arginine or metformin could potentially serve as a adjunctive therapy for preventing bone loss in elderly individuals.

For the treatment of OA, the challenge lies in maintaining cartilage homeostasis by alleviating cartilage degeneration and promoting its regeneration. Sparcl1 is a matricellular protein that mediates cell–matrix interactions. Miao et al. found that Sparcl1 levels were increased in OA cartilage compared to undamaged cartilage [4]. Recombinant Sparcl1 protein induced extracellular matrix degradation in a mice model with anterior cruciate ligament transaction (ACLT) by activating the TNF/NF-κB pathway. These results suggest that SPARCL1 could be a potential therapeutic target for OA. Fang et al. reported that Sipeimine (Sip), a steroidal alkaloid derived from Fritillariae Cirrhosae Bulbus, can alleviate subchondral remodeling and cartilage degeneration in a mouse model of OA [5]. Mechanistic studies revealed that Sip can suppress the PI3K/AKT/NF-κB pathway, thereby inhibiting NLRP3 inflammasome activation and pyroptosis. Zhang et al. investigated the role of cartilage stem/progenitor cells (CSPCs) in maintaining cartilage homeostasis [6]. They found that a subset of human CSPC derived from OA patients exhibited impaired chondrogenic differentiation, decreased lubricin expression and downregulated Yes-associated protein (YAP). Further studies revealed that overexpression of YAP improved proliferation and lubricin production in OA hCSPCs, while upregulation of YAP delayed OA progression and improved cartilage regeneration capacity in a rat model. The repair of osteochondral defects faces challenges when reconstructing the osteochondral interface. In one study, Meng et al. developed laser micropatterned osteochondral implants (LMP-OIs) with natural interface units to repair osteochondral defects in a goat model [7]. At 6 and 12 months after implantation, imaging and histological assessments showed significant improvements in the healing of both cartilage and subchondral bone.

Excessive reactive oxygen species (ROS) is a crucial inter-mediator in the pathogenesis of IDD. In a study authored by Jia et al. [8], umbilical cord mesenchymal stem cells derived exosomes (UCMSC-exos) were used to treat IDD by suppressing ROS production. It was found that UCMSC-exos not only reduced the intracellular ROS, but also increased mitochondrial membrane potential in pathological nucleus pulposus cells. In vivo results also showed that UCMSC-exos injection enhanced the expression levels of collagen type II alpha-1 and histological appearance in a rat IDD model. Jing et al. illustrated a new mechanism of IDD by investigating the intracellular iron levels in the chondrocytes from cartilage endplate of mice model [9]. Excessive iron accumulation was found not only induces chondrocytes ferroptosis and exacerbates oxidative stress, but also triggers the innate immune response mediated by c-GAS/STING. The inhibition of STING through siRNA or the reduction of mtDNA replication alleviated the degeneration of chondrocytes induced by iron overload. The results indicated that targeting TFR1 to maintain balanced iron homeostasis could offer a promising therapeutic approach for IDD patient.

This issue includes two review papers. Xie et al. summarize the adverse effect of smoking on mesenchymal stem cells, osteoblasts, and osteoclasts [10]. The mechanism of smoking-induced periodontitis, rheumatoid arthritis, delayed bone fracture union, and inflammatory bowel diseases was elucidated from an osteoimmune perspective. Wang et al. conduct a systematic review to analyze the effects of physical exercise on neuromuscular junction (NMJ) degeneration during aging [11]. Their findings reveal distinct adaptive responses in aged NMJs compared to younger counterparts when exposed to physical exercise. Specifically, endurance training exhibits a more pronounced effect on NMJ structural remodeling in fast-twitch muscle fibers compared to resistance and voluntary exercise regimens.

Collectively, this issue covers the studies on epidemiology, underlying mechanisms, and new therapeutic interventions for musculoskeletal disorders, especially in elderly populations. All these findings are appealing and show good translational potential, However, comprehensive pre-clinical evaluations are needed to establish a foundation for clinical application.