Osteoarthritis (OA) is characterized by cartilage degeneration and destruction, leading to joint ankylosis and disability. The major challenge in diagnosing OA at early stage is not only lack of clinical symptoms but also the insufficient histological and immunohistochemical signs. Alteration in cartilage stiffness during OA progression, especially at OA initiation, has been confirmed by growing evidences. Moreover, the stiffness of cartilage extracellular matrix (ECM), pericellular matrix (PCM) and chondrocytes during OA development are dynamically changed in unique and distinct fashions, revealing possibly inconsistent conclusions when detecting cartilage matrix stiffness at different locations and scales. In addition, it will be discussed regarding the mechanisms through which OA-related cartilage degenerations exhibit stiffened or softened matrix, highlighting some critical events that generally incurred to cartilage stiffness alteration, as well as some typical molecules that participated in constituting the mechanical properties of cartilage. Finally, in vitro culturing chondrocytes in various stiffness-tunable scaffolds provided a reliable method to explore the matrix stiffness-dependent modulation of chondrocyte metabolism, which offers valuable information on optimizing implant scaffolds to maximally promote cartilage repair and regeneration during OA. Overall, this review systematically and comprehensively elucidated the current progresses in the relationship between cartilage stiffness alteration and OA progression. We hope that deeper attention and understanding in this researching field will not only develop more innovative methods in OA early detection and diagnose but also provide promising ideas in OA therapy and prognosis.

Thus far, there are more than known 150 modifications to RNA，in which common internal modifications of mRNA include N6-Methyladenosine(m6A), N1-methyladenosine(m1A) and 5-methylcytosine (5-mC). Among them, m6A RNA modification is one of the highest abundance modifications in eukaryotes, regulating mechanisms controlling gene expression at the molecular level. As an invertible and dynamic epigenetic marker, m6A base modification influences almost all vital biological processes, cellular components, and molecular functions. Once the m6A modification process is abnormal, a series of diseases -including cancer, neurological diseases, and growth disorders -will be caused. Besides, several base modification activities also have been existed by non-coding RNAs, for instance, microRNAs (miRNAs), and circular RNAs (circRNAs) ，long non-coding RNAs (lncRNAs), which dynamically regulated during Bone and cartilage Pathophysiology processes. Therefore，it has now been clear that dynamic modification on coding RNAs and non-coding RNAs represents a completely new way to modulate genetic information. In this review, we highlight up-to-date progress and applications of N6-methyladenosine (m6A) RNA modification in bone and cartilage pathophysiology, and discuss the pathological roles and underlying molecular mechanism of m6A modifications in osteoarthritis and osteoporosis pathogenesis.

Myotubes are mature muscle cells that form the basic structural element of skeletal muscle. When stretching skeletal muscles, myotubes are subjected to passive tension as well. This lead to alterations in myotube cytophysiology, which could be related with muscular biomechanics. During the past decades, much progresses have been made in exploring biomechanical properties of myotubes in vitro. In this review, we integrated the studies focusing on cultured myotubes being mechanically stretched, and classified these studies into several categories: amino acid and glucose uptake, protein turnover, myotube hypertrophy and atrophy, maturation, alignment, secretion of cytokines, cytoskeleton adaption, myotube damage, ion channel activation, and oxidative stress in myotubes. These biomechanical adaptions do not occur independently, but interconnect with each other as part of the systematic mechanoresponse of myotubes. The purpose of this review is to broaden our comprehensions of stretch-induced muscular alterations in cellular and molecular scales, and to point out future challenges and directions in investigating myotube biomechanical manifestations.

Previously, we had shown that high magnitude stretch (HMS), rather than low magnitude stretch (LMS), induced significant apoptosis of skeletal muscle C2C12 myoblasts. However, the molecular mechanism remains obscure. In this study, we found that p53 protein accumulated in the nucleus of LMS-loaded cells, whereas it translocated into mitochondria of HMS-loaded cells. Knocking down endogenous p53 by shRNA abrogated HMS-induced apoptosis. Furthermore, we demonstrated that overaccumulation of reactive oxygen species (ROS) during HMS-inactivated AKT that was activated in LMS-treated cells, which accounted for the distinct p53 subcellular localizations under HMS and LMS. Blocking ROS generation by N-acetylcysteine (NAC) or overexpressing constitutively active AKT vector (CA-AKT) inhibited HMS-incurred p53 mitochondrial translocation and promoted its nuclear targeting. Moreover, both NAC and CA-AKT significantly attenuated HMS-induced C2C12 apoptosis. Finally, we found that Ser389 phosphorylation of p53 was a downstream event of ROS-inactivated AKT pathway, which was critical to p53 mitochondrial trafficking during HMS stimuli. Transfecting p53-shRNA C2C12s with the mutant p53 (S389A) that was unable to target p53 to mitochondria underwent significantly lower apoptosis than transfection with wild-type p53. Altogether, our study uncovered that mitochondrial localization of p53, resulting from p53 Ser389 phosphorylation through ROS-inactivated AKT pathway, prompted C2C12 myoblast apoptosis during HMS stimulation.

Appropriate orthopedic force led to bone remodeling of mandibular condyle, while overloaded orthopedic force (OOF) induced condylar bone absorption. Bone absorption is ascribed to the imbalanced activities between osteoclasts and osteoblasts, mechanism of which remains unclear. This study aimed to observe the condylar changes induced by overloaded orthopedic force by mandible advancement appliance and to further investigate the role of mTOR and RANKL/OPG in osteoclastic differentiation of stem cells in vivo and in vitro. In vivo, the results of micro-CT analysis indicated that condylar bone resorption was induced by OOF through mandibular advancement appliance since 2 weeks and worsened time-dependently. Morphologically, cartilage thickness was reduced, subchondral cortical bone line appeared uncontinuous, subchondral bone exhibited irregular-shaped and owned uneven surface. The bone mineral density (BMD), bone volume fraction (BV/TV), trabecular number (Tb.N), trabecular thickness (Tb.Th) decreased accomplished with the increased Trabecular separation (Tb.Sp) determined by micro-CT. Additionally, based on immunofluorescent labeling, OOF activated both osteoclasts and osteoblasts, but osteoclastogenesis prevailed over osteogenesis. The mTOR activation and ratio of RANKL/OPG in osteoblasts (OBs) were elevated by OOF. In vitro, the results of Western blot and PCR consistently suggested that the mTOR and RANKL/OPG ratio were upregulated by overloaded mechanical stretch. Pretreatment with mTOR inhibitor, rapamycin, could attenuate the activation of mTOR and the secretion of RANKL in OBs. Interestingly, based on the Trap staining, the supernatant of OBs exposed to OOF could promote osteoclastic differentiation of mesenchymal stem cells (MSCs), while its role was weakened by inhibition of mTOR in OBs. Collectively, OOF induced condylar bone absorption, in the process, osteoclastogenesis was prominent than osteogenesis. The activation of mTOR and secretion of RANKL/OPG was enhanced by OOF and involved in promoting MSCs differentiating into osteoclasts.