Mechanical stress is an important factor affecting bone tissue homeostasis. We focused on the interactions among mechanical stress, glucose uptake via glucose transporter 1 (Glut1), and the cellular energy sensor sirtuin 1 (SIRT1) in osteoblast energy metabolism, since it has been recognized that SIRT1, an NAD+-dependent deacetylase, may function as a master regulator of the mechanical stress response as well as of cellular energy metabolism (glucose metabolism). In addition, it has already been demonstrated that SIRT1 regulates the activity of the osteogenic transcription factor runt-related transcription factor 2 (Runx2). The effects of mechanical loading on cellular activities and the expressions of Glut1, SIRT1, and Runx2 were evaluated in osteoblasts and chondrocytes in a 3D cell–collagen sponge construct. Compressive mechanical loading increased osteoblast activity. Mechanical loading also significantly increased the expression of Glut1, significantly decreased the expression of SIRT1, and significantly increased the expression of Runx2 in osteoblasts in comparison with non-loaded osteoblasts. Incubation with a Glut1 inhibitor blocked mechanical stress-induced changes in SIRT1 and Runx2 in osteoblasts. In contrast with osteoblasts, the expressions of Glut1, SIRT1, and Runx2 in chondrocytes were not affected by loading. Our present study indicated that mechanical stress induced the upregulation of Glut1 following the downregulation of SIRT1 and the upregulation of Runx2 in osteoblasts but not in chondrocytes. Since SIRT1 is known to negatively regulate Runx2 activity, a mechanical stress-induced downregulation of SIRT1 may lead to the upregulation of Runx2, resulting in osteoblast differentiation. Incubation with a Glut1 inhibitor the blocked mechanical stress-induced downregulation of SIRT1 following the upregulation of Runx2, suggesting that Glut1 is necessary to mediate the responses of SIRT1 and Runx2 to mechanical loading in osteoblasts.

Exercise increases oxidative stress, leading the body to strengthen its antioxidant defenses, thus reducing the incidence of major diseases. As these associations are relatively unclear for ordinary levels of exercise for reduced stress, this study evaluated the effects of different exercise conditions on diacron-reactive oxygen metabolites (d-ROMs), biological antioxidant potential (BAP), and subjective mood. Forty-nine students (22.4 ± 2.6 years) were assessed using the Profile of Mood States (POMS) before and after exercising for 60 min. Participants were divided into two groups: Group A engaged in compulsory sports and Group B in freely chosen sports. d-ROMs and BAP were measured, and their modified ratio was calculated as an index of antioxidant potential. Physiological evaluation showed significant improvements in BAP and the BAP/d-ROMs ratio, irrespective of exercise condition (p < 0.001, p < 0.01). Comparison between the exercise conditions revealed a significant difference in the modified ratio (p < 0.02). In mood assessment, scores on emotion-related scales without vigor improved significantly under both exercise conditions (p < 0.001). Mental changes were evident after exercise, and potential antioxidant capacity was higher in freely chosen sports (p < 0.03). Assessment of antioxidant status before and after exercise may provide an objective index of mental and physical conditioning.

Bone resorption and formation are known to change in response to mechanical stress. The mechano-transduction mechanism by which bone tissue senses the stress, altering cellular activity in response via intracellular signaling pathways, ultimately leading to physiological and pathological changes, is beginning to be elucidated. Furthermore, excessive mechanical stress on bone and joints due to aging, obesity, overload, and overuse is thought to cause decreased chondrocyte activity, degeneration and destruction of the cartilage collagen matrix, degeneration of the subchondral bone, and joint dysfunction, contributing to the progression of osteoarthritis (OA). However, much remains unknown about how osteoblasts, responsible for bone formation, and chondrocytes, responsible for cartilage homeostasis, sense and respond to mechanical stress. Furthermore, whether there are mechanisms to protect against pathological and excessive mechanical stress in bone and cartilage tissue, their associated molecular mechanisms, and the relationship between mechanical stress responses and osteochondral degeneration, remain unknown. Understanding these mechanisms is considered essential for the development of new therapeutic strategies for osteochondral diseases. Our research aims to deepen our understanding of the etiology and pathophysiology of bone and cartilage diseases (osteoporosis, fragility fracture, and OA) and to develop new treatments from the perspective of mechanical stress response. In this paper we review the latest findings regarding the roles of cellular energy regulators (glucose transporters and energy sensors) and mechanical stress response factors, and the relationship between these factor-mediated changes in energy metabolism and osteochondral degeneration. This minireview discusses how energy metabolism regulators control the activity of both osteoblasts and chondrocytes in osteochondral tissue in response to mechanical stress.

Mechanical stress is thought to be involved in the pathogenesis and pathophysiology of osteoarthritis (OA). However, much remains to be elucidated regarding how chondrocytes sense and respond to mechanical stress (stress sensing and response factors). Additionally, it still remains unclear whether there are defensive responses and mechanisms to protect against pathological agents and mechanical stress in articular cartilage tissue. This study was designed to determine whether repetitive mechanical force, at physiologic levels, affects the expression of factors regulating autophagy such as the autophagy-related proteins ATG5, Beclin-1, and Parkin, and the autophagy process as well as cellular activity in cultured chondrocytes. Three-dimensional cultured tissue was generated from human chondrocytes using a collagen sponge scaffold. After physiological mechanical loading of the 3D cell–collagen sponge construct, comparative analyses of expression levels of ATG5, Beclin-1, and Parkin were performed in human chondrocytes. Chondrocyte activity and Transmission Electron Microscopy (TEM) analysis for detecting autophagy process were also analyzed with or without repetitive compressive loading. In chondrocytes, 60 min or 180 min repetitive compressive loading significantly decreased the expression of ATG5, Beclin-1 and Parkin in comparison with the non-loading group. TEM analysis indicated that, in normal chondrocytes of the non-loading group, the autophagy process was shown to be progressing. In contrast, repetitive loading decreased the number of autophagosomes and autolysosomes in chondrocytes. In addition, numerous degenerated organelles that had not undergone autophagy were observed within the chondrocytes under repetitive loading. The ATG5 and Beclin-1 proteins are known to play crucial roles in regulating cellular autophagy. Furthermore, repetitive mechanical loading caused a decreased expression of Parkin, a mitophagy regulator in chondrocytes. Our results indicate for the first time that a decrease in mitophagy, as well as cellular autophagy, in response to mechanical stress, even at the physiologic level, leads to the accumulation of defective mitochondria and abnormal cellular proteins, resulting in reduced chondrocyte activity and affecting the maintenance of cartilage tissue homeostasis, ultimately contributing to the progression of OA.

The balance of mental, physical, and technical aspects is essential in improving ballet performance. Ballet dancers’ emotional and behavioral characteristics vary, even under identical stress conditions. This study aimed to investigate the association between the pain candidate genes 5-HTTLPR and COMT and anxiety in Japanese ballet dancers. Participants were 18 youth elite ballet students with professional aspirations (Y-Elite) and 16 dancers in a professional ballet company (Pro). We administered psychological questionnaires, the State-Trait Anxiety Inventory (STAI) and Brunel Mood Scale (BRUMS), to participants under the following four different stress conditions: standard practice day, cast decision day, rehearsal day, and one week before competition day. In addition, the genotypes of 5-HTTLPR and COMT Val158Met were examined. The distribution of 5-HTTLPR was not different between Y-Elite and Pro dancers, although one of the COMT genotypes was different. Y-Elite dancers had higher trait anxiety scores than Pro dancers for these genotypes before competition (ps < 0.03), although no significant association was observed between both genotypes and scores on the STAI across conditions. Their moods were significantly different through the four conditions (p < 0.004). Pro dancers’ moods were also more stable than those of the Y-Elite dancers in the presence of pain. The results indicate that 5-HTTLPR and COMT play a crucial role in dancers’ anxiety and mood during pain (ps < 0.05). Pro dancers are probably predicted by their lower neuroticism and mood scores and their better adaptation to stress than Y-Elite dancers. The 5-HTTLPR and COMT genes may be influencing the sensitivity to the environment. Youth elite ballet dancers need to understand the relationship between pain and physical activity from an early stage.

Bone metabolism is known to change in response to mechanical stress. In osteoarthritis (OA), the subchondral bone as well as the articular cartilage layer is damaged by mechanical stress, which adversely affects the mechanical environment and homeostatic balance of the entire joint, leading to the onset of OA. However, the impact of mechanical stress on osteoblasts in the subchondral bone, especially their defense mechanism against stress, remains unclear. We focused on the mechanical stress response capacity of subchondral bone osteoblasts, which, like chondrocytes in the cartilage layer, are routinely exposed to repetitive mechanical stress. The purpose of this study was to determine whether repetitive mechanical force (at a physiologic level of cyclic compressive loading) affects the expression of factors regulating autophagy, autophagy capacity and cellular activity in subchondral osteoblasts. Three-dimensional cultured tissue was generated from human subchondral bone osteoblasts using a collagen sponge scaffold. Repetitive compressive loading was applied to the 3D cell culture constructs. After mechanical loading on 3D cell–collagen sponge constructs, we comparatively analyzed the expression of autophagy-related factors (ATG5, Beclin-1, Parkin) in human osteoblasts. Levels of osteoblast differentiation activity (alkaline phosphatase) were also analyzed, and transmission electron microscopy (TEM) was used to detect autophagy processes with or without the repetitive compressive loading. In both premature and mature osteoblasts, repetitive compressive loading decreased expression of the autophagy-related factors ATG5, Beclin-1 and Parkin in comparison with the non-loading group, suggesting that repetitive compressive loading may induce downregulation of mitophagy as well as cellular autophagy in subchondral osteoblasts. TEM analysis indicated that, in both premature and mature osteoblasts of the non-loading group, autophagy processes were progressing. In contrast, repetitive loading decreased the number of autophagosomes and autolysosomes in mature and premature osteoblasts. Our results demonstrated that repetitive mechanical loading resulted in a reduction in cellular autophagy and mitophagy in both premature and mature osteoblasts, while also inducing osteoblast differentiation. While mechanical stress promotes osteoblast differentiation, it also alters autophagy, a cellular defense mechanism, suggesting that under conditions of sustained repetitive loading, alterations in the autophagy response—which is essential for maintaining intracellular homeostasis—occur alongside the adaptive bone-forming response, potentially affecting osteoblast function in the long term. Our data demonstrate that reductions in both mitophagy and cellular autophagy in response to repetitive mechanical stress, even at a physiologic level, may lead to accumulation of defective mitochondria and abnormal cellular proteins in the cells, thus reducing osteoblast activity and affecting the homeostasis of subchondral bone tissue, and ultimately contributing to OA progression.