Musculoskeletal disorders (MSDs) are major health problems globally (1). For example, data from the Global Burden of Disease Study 2019 showed that about 1.71 billion people worldwide suffer from MSDs, and MSDs are the highest contributors to years of life lived with disability (2). These diseases not only bring severe individual consequences such as disability, poor quality of life, and sickness absence but also impose a major economic burden on society (3). For example, the total cost of lost productivity attributable to MSDs was approximately 240 billion euros in the EU, up to 2% of the gross domestic product (GDP) (3).

Biomechanical factors (e.g., postural load) are considered as risk factors for MSDs (4). Static postures refer to physical exertion in which the same posture or position is held throughout the exertion. These types of exertions usually put a low level of sustained loads or forces on the muscles and tendons. Static postures mainly occur in occupational activities such as sitting, standing, prolonged bent or twisted posture of trunk, neck, or wrists, working with hands above shoulder level, kneeling or squatting posture (5). Prolonged postures can lead to static loading of the muscles and joint tissues and cause discomfort (6). Previous studies have shown that occupational activities requiring static loading of muscles and joint tissues constitute risk factors for the development of MSDs (7, 8). With the improvement of production mechanization and automation, as well as the widespread application of computers, more occupations are exposed to static postures and load (9, 10). Although the association between static postures and MSDs has been observed in humans, most studies are cross-sectional. There is a lack of human longitudinal studies on the causal relationship between static postures and MSDs.

Despite epidemiological evidence for the role of repetition, force, and postural load in the onset and progression of MSDs, complete understanding of these important health problems requires further elucidation of the pathophysiological mechanisms of MSDs. The National Occupational Research Agenda for Musculoskeletal Health emphasizes the need for etiologic research in determining the contribution of biomechanical mechanisms toward the development of tissue injury and MSDs, as well as strategies to reduce their severity (11). However, the mechanisms leading to pathophysiological tissue changes associated with MSDs are still incompletely understood.

The inflammation in musculoskeletal tissues may be an essential element in the pathogenesis of MSDs (12, 13). In a small number of studies, the severity of upper extremity MSDs has been positively associated with serum levels of tumor necrosis factor-alpha (TNF-α), interleukin-1alpha (IL-1α), interleukin-1beta (IL-1β) and interleukin- 6 (IL-6) in patients (14, 15). Freeland et al. have found higher levels of IL-6 and prostaglandin E₂ (PGE₂) in flexor tendon synovium in patients with carpal tunnel syndrome than in healthy controls (16). In addition, previous studies have also shown increased levels of TNF-α, IL-1α, IL-1β, and IL-6 in serum and muscle tissue in animals with injuries of the upper forelimb caused by excessive repetitive tasks (17, 18). The results of these studies suggested that inflammation may play an essential role in the course of MSDs. Therefore, it is plausible to hypothesize that static postures mediate or aggravate the occurrence of MSDs through inflammatory pathways. In light of the above findings, in this study, we aimed to explore the role of inflammation in the association between static postures exposure and MSDs based on a prospective nested case-control study.

In this study, we investigated the role of inflammation in the association between static postures exposure and MSDs based on a prospective nested case-control study. The major findings of our study include that: (a) the postural load, PPTs, and serum inflammatory cytokines were associated with lower back MSDs among university employees exposed to static postures, (b) the postural load was associated with inflammatory cytokines among university employees exposed to static postures, c) by the use of mediation analysis, we found that postural load affected lower back MSDs through inflammatory cytokines.

Our study showed a positive correlation between postural load and lower back MSDs among university employees exposed to static postures, which is consistent with previous studies (8, 22). A plausible hypothesis, which has been proposed previously and is supported by our findings, is that long-term static postures may change the internal biomechanical loading level or muscle tissue tolerance level by adjusting the physiologic reaction of the muscles, resulting in the internal biomechanical loading exceeding the tolerance of muscle tissues, which will cause tissue damages and lead to the occurrence of MSDs (23).

Another finding in our study was that lower back MSDs were associated with increased pain sensitivity. A previous systematic review and meta-analysis did not find such a significantly lower pain threshold among office workers with chronic neck pain when compared with healthy controls (24). But there is at least one study with findings in line with our study, that is a study of patients with carpal tunnel syndrome which showed a lower pain threshold than healthy controls (25). Our study also found musculoskeletal pain was associated with an increase in inflammatory cytokines. Previous studies have shown that inflammatory cytokines may be related to pain sensitivity, and inflammation may play an important role in the progression of pain (26, 27). For example, a few studies have indicated that higher plasma levels of pro-inflammatory cytokines TNF-α, IL-6, and IL-8 may be related to higher pain sensitivity (28, 29). The reason that inflammatory cytokines may affect the increase of pain sensitivity may be induced by the sensitization of peripheral nociceptors by pro-inflammatory mediators (30). It has also been shown that pro-inflammatory mediators, like cytokines signal the brain via humoral, vagal, and spinal pathways and induce symptoms of sickness behavior, including pain amplification (29). For example, TNF-α regulates the sensitivity of nociceptive neurons through potassium, sodium, and calcium ion channels, thus possibly participating in the pain pathway (31). IL-1β in addition to inducing inflammatory reaction, also directly activates nociceptors to generate action potentials and induce pain hypersensitivity (32). IL-6 may be involved in microglial and astrocytic activation and in the regulation of neuronal neuropeptide expression, and then induce pain hypersensitivity (33). PGE₂ may cause pain by directly exciting nociceptive nociceptors and indirectly stimulating the release of pain-related neuropeptides, such as substance P and calcitonin gene-related peptides from nociceptors and their central and peripheral terminals (34).

Cytokines are proteins involved in many cellular processes, which are the chief stimulators of acute-phase-response proteins and contribute to the development and remediation of signs and symptoms of acute and chronic inflammation, such as the recruitment of immune cells. The increase of pro-inflammatory cytokines in serum indicates a chronic and/or systemic inflammatory reaction in the body. The cytokines TNF-α, IL-1, and IL-6 are intercellular signaling polypeptides produced by most injured cells and activated immune cells, including activated monocytes and macrophages (35). TNF-α and IL-1 can potently stimulate immune and stromal cell production of other cytokines and chemokines as well as most mechanisms of inflammation, including phagocyte proliferation and activation, adhesion, and angiogenesis (35). IL-6, a pleiotropic cytokine, has many pro-inflammatory effects that overlap with those of IL-1 and TNF-α. TNF-α and IL-1β are not influenced by the glycogen content of skeletal muscle and thus are not elevated in serum during exercise unless tissue damage has occurred (36). IL-6 is a tightly regulated cytokine normally not detectable in serum unless there is injury, infection, or cellular stress (12). PGE₂ is a factor believed to cause vasodilation, edema, and increased release of inflammatory cytokines. When tissue injury occurs, PGE₂ is produced by a large number of inflammatory cells in inflammatory tissue, which plays an essential role in the process of inflammation and pain.

Mediation analysis in the population provided an indication that postural load may affect the occurrence of MSDs through inflammatory cytokines such as TNF-a and IL-6. These new findings showed that there may be the participation of tissue inflammatory and systemic inflammation in the process of MSDs induced by static postures, which is in agreement with previous studies of repetitive tasks and exercise-induced skeletal muscle injuries (17, 18). Elevated systemic inflammation induces a pro-inflammatory response in tissues, such as muscles at the injury site (37). Conversely, inflamed tissues secrete inflammatory cytokines that contribute to systemic inflammation (38). This self-perpetuating cycle could underpin a chronically elevated inflammatory state with profound effects on the physiology and structure of musculoskeletal tissues, including connective tissues (39, 40).

To our best knowledge, this is an innovative study linking static postures and MSDs through a viewpoint of inflammatory pathways. The main strengths of our study are its prospective cohort-based, nested case-control design, which minimized selection bias and information bias. Our study provides evidence for the potential mechanism of increased MSDs risks associated with static postures exposure. Moreover, the increase of inflammatory cytokines may be a critical early event in MSDs progression and intervention target for the primary prevention of MSDs. Further studies are needed to investigate if preventing the occurrence of inflammation contributes to reducing the development of MSDs. However, several limitations should be noted. Firstly, variables may be influenced by subjective factors, and more objective methods such as clinical examination and special tests (such as surface electromyography) should be used in future research (41, 42). Secondly, the sample size of our study is limited, and it is quite advisable to include more occupational populations exposed to static postures to verify the results in future studies.

Long-term static postures are closely related to the occurrence of MSDs through a viewpoint of inflammatory pathways, and low-level inflammation may be a critical early event in the generation of MSDs. Our findings may help bridge the gap of potential mechanisms linking static postures to increased risks of MSDs, and provide new evidence for targeted protection against the globally increasing MSDs. In addition, this study can likely contribute to the prevention of MSDs and improved health of the occupational population.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The studies involving human participants were reviewed and approved by Institutional Review Board of Peking University. The patients/participants provided their written informed consent to participate in this study.

YD, YS, and LH were responsible for the study conceptualization, methodology development and validation, and study supervision. YD, PJ, XJ, NJ, and WH contributed to the conduction of population surveys. YD and PJ contributed to the preparation of samples and molecular biology experiments. YD contributed to the biostatistical analysis and interpretation and drafting of the manuscript. YD, XJ, NJ, WH, MF, and LY contributed to the critical revision of the manuscript for important intellectual content. All authors have read and approved the final version of the manuscript and agreed with the order of presentation of the authors.

This study was supported by Foundation strengthening program of China (2020JCJQJJ238) and National Key Technologies Research and Development Program of China (2016YFC0801700).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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