Emerging role and function of Hippo-YAP/TAZ signaling pathway in musculoskeletal disorders

Abstract

Hippo pathway is an evolutionarily conservative key pathway that regulates organ size and tissue regeneration by regulating cell proliferation, differentiation and apoptosis. Yes-associated protein 1 (YAP)/ WW domain-containing transcription regulator 1 (TAZ) serves as a pivotal transcription factor within the Hippo signaling pathway, which undergoes negative regulation by the Hippo pathway. The expression of YAP/TAZ affects various biological processes, including differentiation of osteoblasts (OB) and osteoclasts (OC), cartilage homeostasis, skeletal muscle development, regeneration and quality maintenance. At the same time, the dysregulation of the Hippo pathway can concurrently contribute to the development of various musculoskeletal disorders, including bone tumors, osteoporosis (OP), osteoarthritis (OA), intervertebral disc degeneration (IDD), muscular dystrophy, and rhabdomyosarcoma (RMS). Therefore, targeting the Hippo pathway has emerged as a promising therapeutic strategy for the treatment of musculoskeletal disorders. The focus of this review is to elucidate the mechanisms by which the Hippo pathway maintains homeostasis in bone, cartilage, and skeletal muscle, while also providing a comprehensive summary of the pivotal role played by core components of this pathway in musculoskeletal diseases. The efficacy and feasibility of Hippo pathway-related drugs for targeted therapy of musculoskeletal diseases are also discussed in our study. These endeavors offer novel insights into the application of Hippo signaling in musculoskeletal disorders, providing effective therapeutic targets and potential drug candidates for treating such conditions.

Introduction

Hippo pathway is a key regulatory cascade to control tissue growth, which coordinates organ size by precisely controlling cell proliferation, differentiation and survival [1–3]. When the Hippo pathway is activated, Yes-associated protein 1 (YAP)/WW domain-containing transcription regulator 1 (TAZ) activity is suppressed and YAP/TAZ are sequestered or degraded in the cytoplasm. Conversely, when Hippo signaling is deactivated, unphosphorylated YAP/TAZ translocate and accumulate in the nucleus, where they interact with TEA domain (TEAD) transcription factors to regulate target gene expression and activate genes that facilitate cell proliferation and survival [4–7]. Therefore, Hippo pathway is a signal cascade closely related to cell proliferation and differentiation. The fundamental constituents of the Hippo pathway govern tissue growth homeostasis and regeneration, while aberrations in this pathway can result in uncontrolled cell proliferation, malignant transformation, and tissue dysfunction, thereby contributing to the development of various diseases. For instance, dysregulation of Hippo signaling augments YAP/TAZ expression and fosters tumorigenesis [8].The upregulation of YAP expression enhances osteoblast (OB) activity and suppresses osteoclast (OC) activity, thereby promoting bone formation and inhibiting bone resorption, ultimately ameliorating osteoporosis (OP) [9].In addition to the core components of Hippo, upstream factors such as TAO kinase and neurofibrin-2 (NF2) also redundantly contribute to tissue regulation within the intricate framework of the Hippo pathway [10, 11].

Musculoskeletal diseases are a group of inflammatory and degenerative conditions resulting from damage or pain in the motor organs, primarily affecting the musculoskeletal system, including bones, cartilage, and muscles. This encompasses various disorders such as bone tumors, OP, osteoarthritis (OA), intervertebral disc degeneration (IDD), rhabdomyosarcoma (RMS), and muscular dystrophy [12].The prevalence of musculoskeletal diseases has been steadily increasing in recent years, emerging as a significant contributor to global disability rates and imposing substantial burdens on both healthcare systems and social welfare networks worldwide [13, 14]. However, the precise pathogenesis remains elusive, and there is a lack of effective treatment currently. Increasing evidence suggests a close association between the Hippo pathway and musculoskeletal system, Hippo pathway could maintain bone, cartilage and skeletal muscle homeostasis by regulating a series of signal pathways and transcription factors, such as Wnt/β-catenin, nuclear factor-κb (NF-κB), runt-related transcription factor 2 (RUNX2) and myogenic regulatory factors(MRFs) [15–18].Moreover, a large number of studies have reported that Hippo pathway is involved inregulating the occurrence and development of musculoskeletal diseases. Compared with normal tissues, YAP/TAZ is up-regulated in cancer diseases such as bone tumors and RMS, which promotes the proliferation, migration and invasion of cancer cells [19–23].However, the expression of YAP/TAZ can maintain the balance between bone formation and bone absorption, and the balance between adipogenesis and osteogenesis, so it is a promising target for the prevention and treatment of OP [9, 24].Hippo pathway can also regulate the development of OA, IDD and muscle atrophy. Furthermore, the Hippo pathway also represents a promising and dependable dual-target approach for managing musculoskeletal disorders. At present, many drugs targeting YAP/TAZ have been used to treat musculoskeletal diseases. For example, the porphyrin compound Vitipofen (VP) is the only YAP/TAZ direct inhibitor so far, which shows promising therapeutic value for bone tumors, RMS and OA [25, 26].Overall, this paper summarizes the key role of Hippo pathway in the growth and development of bone, cartilage and skeletal muscle, and summarizes its role in musculoskeletal diseases. We also discussed the strategy of activating or inhibiting Hippo signal transduction to treat musculoskeletal diseases, hoping that these strategies can provide new methods to treat diseases.

Hippo signaling pathway

Hippo pathway is closely related to many biological processes such as cell growth and death, organ size control and tissue regeneration. The core components of Hippo pathway include upstream kinase cascade transcription and downstream effector factors [27, 28].The key constituents of the mammalian Hippo pathway encompass mammalian STE20-like kinase 1/2 (MST1/2), protein Salvador homologue 1 (SAV1), large tumour suppressor kinase 1/2 (LATS1/2), MOBKL1A/B (MOB1A/B), as well as YAP/TAZ, and DNA-binding protein TEAD1/2/3/4 [29].MST1/2-SAV1 forms a complex, which activates LATS1/2- MOB1A/B complex, and then phosphorylates YAP/TAZ. The phosphorylated YAP/TAZ binds to 14-3-3 connexin and is isolated in the cytoplasm, or degraded in the cytoplasm [4, 30].In summary, the core of Hippo pathway is kinase cascade reaction, which is activated by phosphorylation events, and finally leads to phosphorylation of transcription coactivator YAP/TAZ [31].When YAP/TAZ are dephosphorylated, they translocate to the nucleus for binding with TEAD or other transcription factors, thereby forming a complex that regulates the expression of multiple genes involved in cell proliferation, apoptosis, differentiation, maturation, and migration. When MST1/2, SAV1, LATS1/2 or MOB1A/B are deleted, the nuclear translocation of YAP/TAZ increases and the transcription of their target genes increases. On the contrary, when Hippo pathway is activated, YAP/TAZ expression will decrease [32].Therefore, the protein level of YAP/TAZ and its location in cells are often used to judge the activity of Hippo pathway [33] (Fig. 1).

Fig. 1.

The Hippo pathway in mammals. The key constituents of the mammalian Hippo pathway encompass MST1/2, LATS1/2, SAV1, MOB1, YAP or TAZ and TEAD, with a cascade of phosphorylation events instigating pathway activation. MST1/2 can be activated by TAO1/2/3, NF2 or autophosphorylation. Activated MST1/2 associates with SAV1 to phosphorylate and activate LATS1/2. Subsequently, activated LATS1/2 forms a complex with MOB1 and subsequently phosphorylates YAP/TAZ, leading to sequestration or degradation of YAP/TAZ by 14-3-3 proteins in the cytoplasm. In addition, MAP4K family members (MAP4K1/2/3/5 and MAP4K4/6/) activate the Hippo pathway by promoting the phosphorylation of MST1/2. After the inactivation of Hippo pathway, unpahosphorylated YAP/TAZ translocates into the nucleus, where it interacts with TEAD or other transcription factors to induce gene expression

The activation of classical Hippo signaling pathway is mainly mediated by autophosphorylation of MST1/2 kinase to inhibit the nuclear localization of YAP/TAZ [34, 35].In addition, TAO kinase (TAOK1/2/3) and NF2 can directly phosphorylate MST1/2, thus starting the Hippo kinase cascade. This leads to the isolation of YAP/TAZ in cytoplasm, which effectively limits their activity [10, 11, 36, 37]. In recent years, it has been found that MST1/2 is not indispensable for the adjustment of YAP/TAZ. The mitogen-activated protein kinase technology kinase kinases (MAP4K) family members, namely MAP4K1/2/3/5 and MAP4K4/6/7, which function as parallel kinases to MST1/2, can directly phosphorylate LATS1/2 to induce YAP/TAZ phosphorylation. MAP4K family members and MST1/2 partially overlap to activate LATS1/2, thus inhibiting the nuclear translocation of YAP/TAZ [38, 39].Additionally, the majority of YAP/TAZ proteins exist in a phosphorylated or dephosphorylated state and undergo rapid transport between the cytoplasm and nucleus, rather than remaining in a quiescent state [40].

Hippo-YAP/TAZ signaling pathway in bone biology

Bone is a dynamic tissue, and the bone absorption and formation of the skeletal system are in dynamic balance, which is called bone homeostasis. When the balance between OB-mediated bone formation and OC-mediated bone absorption is interrupted or out of balance, it may lead to OP and other bone metabolism-related diseases. The Hippo pathway plays a role in regulating the differentiation of OB and OC to maintain bone homeostasis (Fig. 2).

Fig. 2.

The Hippo pathway regulates the signaling pathways involved in the differentiation of OB and OC. When the Hippo pathway is activated, phosphorylated YAP/TAZ is sequestered within the cytoplasmic compartment. Conversely, when the Hippo pathway is inactivated, YAP/TAZ translocates into the nucleus to initiate transcriptional activation. Phosphorylated YAP/TAZ not only inhibits Smad phosphorylation and nuclear translocation to block TGF-β signaling and transcription of osteogenesis related genes, but also blocks Wnt signaling and transcription of osteogenesis related genes by inhibiting β-catenin nuclear translocation, inhibiting β-catenin phosphorylation, or forming β-catenin degradation complex. Dephosphorylated YAP/TAZ can directly block RANKL conduction or enhance OPG expression to inhibit RANKL conduction, thus inhibiting RANKL-induced OC differentiation

The differentiation of mesenchymal stem cells into osteoblasts is regulated by many signal pathways, especially Wnt and transforming growth factor β (TGF-β) [41, 42]. YAP/TAZ, as a regulator of osteogenic transcription factors, regulates osteogenic differentiation-related pathways and promotes MSC differentiation into OB [43]. Typical Wnt signaling pathway is activated in the presence of Wnt ligand, releasing β-catenin and activating TCF/LEF for RUNX2 transcription, thus promoting OB differentiation [44, 45].Hippo pathway mainly counteracts Wnt signal by regulating the nuclear translocation of β -catenin, thus regulating the differentiation of MSC into OB. When the Hippo pathway is closed, the up-regulation of YAP expression makes β-catenin translocate to the nucleus, thus increasing the differentiation of OB mediated by nuclear β-catenin, while YAP deficiency is the opposite [15].Similarly, the study in old OP mice once again verified this mechanism. Li et al. found that YAP expression was down-regulated in old OP mice. By up-regulating YAP expression, it was found that YAP located in the nucleus could increase the nuclear accumulation of β-catenin, thus promoting the differentiation of OB, and finally promoting the repair of bone defects in OP mice [46].In addition, Hippo also antagonizes Wnt pathway in other ways. For example, cytoplasm-localized phosphorylated YAP/TAZ binds to disordered fragment polar protein 2(DVL2) which activates Wnt conduction, and inhibits the phosphorylation of DVL2, thus down-regulating Wnt signal and inhibiting the nuclear translocation of β-catenin [47].Phosphorylated YAP/TAZ can also combine with β -catenin degradation complex to enhance the degradation of β -catenin by the complex, or directly combine with β -catenin to isolate it in the cytoplasm and prevent it from transferring to the nucleus for gene transcription [48].YAP/TAZ also regulates Smad signaling, particularly the TGF-β signaling cascade. TGF-β transduction controls Runx2 expression through either canonical Smad-dependent or non-canonical Smad-independent pathways, thereby facilitating OB differentiation and bone formation [42]. YAP/TAZ plays a key role in adjusting the positioning of Samd. Phosphorylated YAP/TAZ inhibits the transcription activity of TGF-β by inhibiting the phosphorylation and nuclear accumulation of Smad2/3, while nuclear-localized YAP/TAZ is the opposite [49].In addition, phosphorylated YAP also significantly enhanced Smad7’ s inhibition of TGF-β/Smad signaling [50, 51].It is found that YAP/TAZ deletion may increase OB activity and decrease OC activity by blocking TGF-β signal transduction, thus destroying bone accumulation [51].These results show that the expression of YAP/TAZ is positively correlated with osteogenesis-related pathways, so it can promote osteogenesis. OC are multinucleated cells that originate from the monocyte/macrophage (MP) lineage and possess the ability to resorb bone tissue. The receptor activator of NF-κB ligand (RANKL) -receptor activator of NF-κB (RANK) -osteoprotegerin (OPG) system serves as the primary regulatory mechanism for OC differentiation, activation, and survival [52–54].Hippo pathway is involved in the regulation of OC differentiation mainly through its downstream effectors YAP/TAZ affecting the NF-κB pathway and the expression of OPG. Yang et al. discovered that in bone, the binding of YAP/TAZ to transforming growth factor beta-activated kinase 1 (TAK1) inhibits the activation of the NF-κB pathway and impedes OC differentiation, thereby suppressing excessive bone resorption and enhancing bone metabolism [16, 24].In addition, the early research on the inhibitor kinase MST1/2 upstream of YAP provides some new insights into the role of the Hippo pathway in OC differentiation. Li’s research found that MST1/2 had a negative regulatory effect on OC differentiation. The absence of MST2 activates NF-κB signaling pathway, thus promoting OC differentiation and inhibiting OB differentiation. On the contrary, the ectopic expression of MST1/2 in OB precursor cells inhibits OC differentiation [55].As a recognized OC inhibitor, the up-regulation of OPG expression significantly inhibits bone resorption [56].It has been proved that the expression of YAP/TAZ promotes the up-regulation of OPG expression, indicating that targeted up-regulation of YAP/TAZ may be an effective strategy to inhibit OC production and enhance bone metabolism [16].In addition, knocking out the binding protein TEAD1 of YAP/TAZ can also down-regulate the expression of OPG and promote the production of OC. It is further proved that Hippo signal transduction affects bone homeostasis by regulating OPG [57].The results show that YAP/TAZ expression is an effective strategy to enhance OB differentiation and inhibit OC differentiation, thus improving bone metabolism.

Hippo-YAP/TAZ signaling pathway in cartilage homeostasis

Cartilage homeostasis is necessary for cartilage to maintain normal morphological structure and biological function. Chondrocytes, extracellular matrix (ECM), synovium and subchondral bone jointly maintain cartilage homeostasis. The destruction of cartilage homeostasis may lead to the development of musculoskeletal diseases, such as OA and IDD. Hippo pathway regulates a series of biological processes in chondrocytes (including differentiation, maturation and apoptosis), ECM degradation, synovial fibroblasts proliferation and subchondral bone remodeling to affect cartilage homeostasis. However, the exact role of YAP/TAZ in cartilage homeostasis is controversial (Fig. 3).

Fig. 3.

Hippo pathway maintains cartilage homeostasis. (A) Hippo regulates chondrocyte differentiation and other processes: YAP/TAZ regulates the proliferation and differentiation of chondrocytes by regulating the expression of Sox5/6/9. The interaction between YAP and RUNX2 inhibits chondrocyte maturation and hypertrophy, while TAZ is just the opposite. YAP expression regulates chondrocyte apoptosis. (B) Hippo regulates ECM degradation: the expression of YAP/TAZ antagonizes the NF-κB pathway and inhibits ECM decomposition, but YAP expression may also up-regulate MMP13 and promote ECM decomposition. (C) Possible role of Hippo in subchondral bone remodeling: Hippo may regulate RANKL and TGF-β pathway and affect subchondral bone remodeling. (D) Regulation of Hippo in synovium: the expression of YAP/TAZ inhibits cartilage degradation by inhibiting the release of proinflammatory factors and the expression of MMPs and ADAMTS caused by FLS hyperproliferation

Articular cartilage lacks blood vessels and nerves, and its internal repair ability is limited, so the preservation of chondrocytes in cartilage is very important for joint health. The differentiation, proliferation, hypertrophy and apoptosis of chondrocytes are the key processes to maintain the health of cartilage tissue [58–60].Chondrocytes are derived from MSC, and Sox5/6/9, a member of high mobility group (HMG)-box(SOX) protein family related to sex-determining region Y(SRY), is a key transcription factor for promoting chondrocyte differentiation and proliferation [61, 62]. Deng et al. discovered that YAP directly upregulated the expression of Sox6 by binding to TEADs, thereby facilitating chondrocyte differentiation and proliferation. Furthermore, they reported a similar effect exerted by TAZ [17].Consistent with this, another study shows that TAZ is necessary for cartilage formation, and it can promote the proliferation and differentiation of chondrocytes by up-regulating SOX5 by combining with TEAD1 [63].However, the role of YAP/TAZ in regulating Sox5/6/9 is still controversial. Another study reported that the over-activation of YAP/TAZ significantly down-regulated the expression of Sox5/6/9 mRNA and protein, resulting in impaired proliferation and differentiation of chondrocytes [64].We speculate that this difference can be attributed to the fact that the YAP knockout mice used by Deng et al. were induced in embryonic stage, not before OA development. Maturation and hypertrophy of chondrocytes are two successive processes. Hypertrophy is a temporary and necessary state, but its persistence will lead to cartilage degeneration [59].The expression of transcription activator RUNX2 contributes to chondrocyte maturation and hypertrophy. Collagen type X α 1 (COL10A1), a marker gene for chondrocyte hypertrophy, is directly regulated by RUNX2 [65].The interaction between YAP and RUNX2 inhibits the expression of COL10A1 and blocks the hypertrophy and maturation of chondrocytes. It is worth noting that TAZ overexpression enhances the transcription activity of COL10A1 [17, 63].ECM is synthesized by chondrocytes, so the increase of chondrocyte apoptosis level can lead to articular cartilage damage [60].Up-regulated YAP effectively inhibited the apoptosis of OA chondrocytes and promoted the proliferation of chondrocytes [66, 67].It has also been reported that YAP is overexpressed in OA tissue, which promotes chondrocyte apoptosis and inhibits chondrocyte proliferation [68].Therefore, the exact role of YAP/TAZ in chondrocyte apoptosis needs to be clarified. The imbalance of ECM synthesis and degradation is a sign of cartilage diseases, such as OA. Proinflammatory cytokines, including tumour necrosis factor-α (TNF-α), interleukin-1β(IL-1β),and Interleukin 6 (IL-6), primarily activate the NF-κB pathway leading to upregulation of matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs), thereby inducing ECM degradation [69–71].The expression of YAP/TAZ has been demonstrated in multiple studies to inhibit ECM degradation [72].Studies have shown that YAP/TAZ expression antagonizes NF-κB signaling pathway, thus preventing ECM degradation and maintaining cartilage homeostasis by inhibiting the expression of MMPs and ADAMTS [73].However, it has also been reported that over-activated YAP leads to up-regulation of MMPs expression and promotes cartilage ECM degradation [74].This discrepancy may stem from differences in the models used. The model used by Liu et al. is Kashin-Beck disease (KBD) hiPS derived chondrocytes (hiPS-Ch).

Healthy synovium is very important to maintain cartilage homeostasis [75].In cartilage lesions, the synovial histological changes are mainly synovial tissue hyperplasia caused by excessive proliferation of fibroblast-like synoviocytes (FLS), which produce large amounts of IL-1β, TNF-α,IL-6, MMPs and ADAMTS, and accelerate ECM degradation [76, 77].Hippo is an important regulator of FLS proliferation, and phosphorylated YAP can effectively inhibit FLS proliferation, thus reducing the transcription level of pro-inflammatory factors and matrix degrading enzymes and delaying the progress of cartilage degradation [78].The enhancement of subchondral bone remodeling will lead to osteosclerosis, and the abnormal mechanical support caused by chondrosclerosis will transfer the increased load to the overlying cartilage, resulting in secondary cartilage damage and degeneration [79, 80].When subchondral osteocytes perceive abnormal mechanical stress or have other causes, they will activate RANKL and TGF-β signal transduction, which alone or jointly lead to osteosclerosis [81, 82].It was found that Hippo pathway can regulate the main signal pathways (RANKL and TGF-β) connecting cartilage and subchondral bone. YAP/TAZ located in the nucleus inhibits RANKL signaling pathway, thus reducing the production of OC, which may further inhibit bone sclerosis [16, 24]. However, YAP/TAZ located in the nucleus can also activate TGF-β signal transduction, which may promote bone remodeling [49].Although there is no specific study on the regulation of subchondral bone by Hippo pathway, these reports show that Hippo pathway has the potential to regulate the bone remodeling of subchondral bone and participate in maintaining cartilage homeostasis. Previous studies fully shows that the Hippo pathway is closely related to cartilage homeostasis, but there are contradictions in the process of chondrocyte proliferation and differentiation and ECM degradation, and there is no report on the regulation of subchondral bone by Hippo pathway, which deserves our in-depth study.

Hippo-YAP/TAZ signaling pathway in muscle biology

Muscle biology mainly refers to skeletal muscle development, regeneration and quality maintenance. The development of skeletal muscle is a highly coordinated process, which is mainly regulated by muscle-derived MRFs. Skeletal muscle is a stable tissue in adulthood, and its lifelong maintenance is regulated by satellite cells (SC). When injured, SC initiates rapid and extensive repair to promote skeletal muscle regeneration, and good muscle regeneration ability can maintain muscle homeostasis. In addition, the quality of skeletal muscle is determined by the balance between protein synthesis and degradation. Hippo pathway plays an important regulatory role in skeletal muscle development, skeletal muscle regeneration and skeletal muscle quality maintenance (Fig. 4).

Fig. 4.

The Hippo pathway is involved in skeletal myogenesis, regeneration after injury, and maintenance of skeletal muscle mass. (A) Hippo regulates myogenesis: YAP/TAZ participates in the proliferation and differentiation of myoblasts by affecting the expression of MRFs, and then affects myogenesis. (B)Hippo in muscle regeneration: YAP/TAZ affects the inflammatory response, the proliferation and differentiation of SCs and the formation of ECM. (C) Hippo in skeletal muscle quality maintenance: YAP expression down-regulates Smad2/3 activity and reduces protein decomposition. It may also promote protein synthesis by reducing PTEN protein level and activating AKT- mTOR pathway

Mammalian skeletal muscle originates from mesoderm, which is also called myogenesis. MFRs including MyoD, Myf5, myogenin (MyoG) and MRF4 play a key role in skeletal muscle development. The expression of MyoD and Myf5 promotes the proliferation of myoblasts. When the proliferating cells exit the differentiation cycle, MyoG and MRF4 participate in the initiation of differentiation, and myoblasts become myoblasts. Then muscle cells and neighboring cells fuse into multinucleated myotubes, which further grow and differentiate to form mature muscle fibers [83].YAP/TAZ plays a positive regulatory role in the proliferation and differentiation of myoblasts by influencing the expression of MFRs. However, in the process of myoblast differentiation, their effects are opposite [84].At present, it has been found that YAP promotes myoblast proliferation by increasing the expression of MyoD and Myf5, but inhibits myoblast differentiation by inhibiting the expression of MRF4 and MyoG [84, 85].YAP has been identified as a new regulator of C2C12 myogenesis, and the phosphorylation of YAP and its transfer from nucleus to cytoplasm are necessary for the final differentiation of myoblasts [86].TAZ promotes the expression of MyoD, Myf5 and MyoG, and plays an active role in the proliferation and differentiation of myoblasts [18, 23, 84].Although there is no research to prove it, we believe that TAZ may also increase the expression of MRF4, thus promoting myoblast differentiation.

Skeletal muscle has remarkable regeneration ability after injury. Skeletal muscle regeneration is a complex process, which requires the synergy of SC, ECM and inflammatory reaction to completely restore muscle structure [87].Skeletal muscle regeneration can be divided into three successive stages: inflammation-induced destruction, activation of SC proliferation and differentiation to form new muscle fibers and remodeling. Finally, the damaged fibers are repaired by the fusion of new muscle fibers and existing muscle fibers, and each stage is essential for the next stage [88–90].Acute skeletal muscle injury will produce rapid and controllable inflammation to eliminate damaged and dead muscle fibers, and premature disappearance of inflammation is not conducive to muscle regeneration and recovery [91, 92].MP activated during injury are usually divided into two categories. The first is pro-inflammatory M1-like MP, whose cells gather in the injured tissue area, phagocytize debris and stimulate the proliferation of satellite cells, and then transform into anti-inflammatory M2-like MP, releasing anti-inflammatory factors and fibrosis-promoting molecules, and then activate fibroblasts to produce ECM to support the formation and growth of new muscle fibers [93–96].YAP/TAZ has been proved to be an important regulator of MP polarization and function. YAP/TAZ is the activator of M1, but it is the repressor of M2. The absence of YAP/TAZ can weaken the early necessary inflammatory reaction by promoting the polarization from M1 to M2, which is not conducive to the regeneration of injured muscles [97].In addition, the lack of YAP/TAZ may not be conducive to the activation of SC during injury, thus hindering muscle regeneration. As a key participant in muscle regeneration, SC is stimulated and activated when muscle fibers are damaged. Through the expression of MyoD and Myf5, SC is transformed into myoblasts and proliferated, then myoblasts are differentiated into myoblasts and fused into myotubes through the expression of MyoG, and finally fused with existing muscle fibers to repair damaged fibers [98, 99]. In the process of new muscle fiber formation, the high expression of YAP/TAZ will promote the expression of Myf5 and MyoD, thus promoting the proliferation of myoblasts, but the over-expression of YAP will inhibit the expression of MyoG and MRF4, thus inhibiting the differentiation of myoblasts, while TAZ will promote the expression of MyoG, thus promoting the differentiation of myoblasts [18, 23, 84, 85].In addition, the rapid formation of skeletal muscle ECM after injury is very important to drive skeletal muscle regeneration. After skeletal muscle injury, fibroblasts are activated, move to the wound for proliferation, deposit temporary ECM for collagen synthesis, and support the broken and damaged muscle fibers during the healing process [100].Hippo pathway is closely related to fibrosis of many tissues. The expression of YAP/TAZ promoted the activation and proliferation of fibroblasts, but when the expression of YAP/TAZ was inhibited, fibrosis was significantly reduced and ECM deposition was inhibited [101, 102].In addition, lysophosphatidic acid (LPA) can promote fibrosis. When skeletal muscle is damaged, dephosphorylation of YAP is necessary for LAP-induced activation of fibrosis-related proteins and fiber/adipogenic progenitor cells (FAP) to produce ECM [103, 104].

The balance of protein synthesis and decomposition speed of muscle determines the quality of skeletal muscle. When protein synthesis exceeds its degradation, it will lead to skeletal muscle hypertrophy, on the contrary, muscular atrophy will occur [105].The maintenance of skeletal muscle quality is mainly regulated by two signal pathways: the insulin-like growth factor 1 (IGF1) -serine/threonine kinase (AKT) -rapamycin (mTOR) pathway as a positive regulator and the myostatin (MSTN) -Smad2/3 pathway as a negative regulator [106, 107].MSTN down-regulates AKT activity to reduce protein synthesis or phosphorylate Smad2/3 to directly increase protein decomposition, leading to muscle atrophy [107, 108].YAP expression can decrease Smad2/3 activity and its induced expression of muscle ring finger 1 (MuRF1), and promote skeletal muscle hypertrophy [109].In addition, when YAP is overexpressed, it can not only directly activate AKT, but also indirectly activate AKT-mTOR pathway by reducing the protein levels of negative regulators-protein phosphatase and tensin homologue (PTEN) upstream of mTOR [110, 111]. Unfortunately, it is not clear whether Hippo can regulate the IGF1-Akt-mTOR pathway to participate in skeletal muscle quality maintenance. We speculate that YAP may play an active role in skeletal muscle mass maintenance through this pathway. Therefore, the expression of YAP/TAZ has a positive role in promoting the development and regeneration of skeletal muscle after injury, and the role of Hippo in maintaining the quality of skeletal muscle deserves our study.

The regulatory role of Hippo-YAP/TAZ signaling pathway in musculoskeletal disorders

Bone tumors

Osteosarcoma (OS) and chondrosarcoma (CS) are common primary bone tumors. OS mainly affects growing teenagers and people aged 50 or above who suffer from bone deformities, while CS mainly affects adults, making it the second most common primary bone solid tumor after OS [112–114].Hippo pathway is a tumor inhibition pathway in mammals, and its imbalance will lead to the occurrence of tumors [115]. A large number of studies have found that Hippo is also involved in the occurrence and development of OS and CS (Table 1; Fig. 5).

Table 1.

Hippo pathway components in musculoskeletal diseases

Disease type	Component	Summary of proposed pathologic role	Reference
Osteosarcoma	YAP/TAZ	Promote OS cell proliferation, invasion and migration	[19, 112–116]
Chondrosarcoma	YAP/TAZ	Positively correlated with CS progression and grading	[117]
	YAP	Promote CS cell proliferation, growth, invasion, migration and inhibit senescence	[20, 118–120]
Osteoporosis	YAP/TAZ	Increase the expression of Ocn, Alp, Bsp and Runx2, and down-regulate PPARγ and inhibition NF-κB pathway	[9, 15, 24, 121–125]
Osteoarthritis	YAP	Up-regulated in OA tissues, inhibit the proliferation and differentiation of chondrocytes, promote the apoptosis of chondrocytes and the expression of ECM decomposition genes such as COL2A1 and MMPs	[68, 126]
	YAP	Inhibiting the increased expression of MMPs and ADAMTS, while increasing the expression of collagen type ii (Col -II) and aggregated proteoglycan (ACAN), and maintaining the balance of proliferation and apoptosis in chondrocytes	[66, 73, 127]
Intervertebral disc degeneration	YAP/TAZ	Inhibits NPC senescence and apoptosis, decreases expression of MMPs and ADAMTS and increases COL2A1 and ACAN mRNA expression	[128–131]
	YAP	Decreased expression of Col -II and ACAN, increased levels of MMPs, formation of transcriptional complexes with β-catenin and translocation into the nucleus, increased apoptosis and ECM catabolism	[132–134]
Alveolar rhabdomyosarcoma	YAP/TAZ	Up-regulated in ARMS tissue leads to increased proliferation and invasion, decreased aging and decreased differentiation of ARMS cells	[22, 135]
Embryonal rhabdomyosarcoma	YAP	Up-regulated in ERMS promotes the continuous proliferation of ERMS cells and interferes with the expression of MyoD and MyoG to maintain ERMS differentiation block	[136, 137]
	TAZ	Drive the expression of oncogene Myf5, and support the proliferation, survival and undifferentiated state of ERMS cell line	[23, 138]
Muscular dystrophy	YAP	Inhibit the expression of Atrogin-1 and MuRF1	[109, 139]
	YAP	Increase the mRNA expression of MuRF1 and Atrogin-1	[140]
	MST1	MST1 deficiency reduces the transcription of Atrogin1 gene dependent on FOXO3a in muscular atrophy	[141]

Fig. 5.

Hippo in bone tumors, OA and OP. (A) Hippo pathway in OS and CS: YAP/TAZ is highly expressed in OS and CS, which promotes the proliferation, invasion and migration of OS and CS cells. (B) Hippo pathway in OP: the regulation of YAP/TAZ expression affects the balance of OB and OC and the balance of adipogenesis and osteogenesis in OP development. (C) Hippo pathway in OA: YAP affects the progress of OA by regulating chondrocyte proliferation, differentiation, apoptosis and ECM degradation, but the exact role is controversial

The distortion of Hippo signaling pathway is very important in the biology of OS. YAP is highly expressed in OS tissues compared with non-cancer tissues, and it is closely related to OS staging, while knocking out YAP prevents the proliferation and invasion of OS cells by down-regulating RUNX2 and inhibiting Wnt signaling pathway [19, 116].In addition, several carcinogenic miRNA and tumor suppressor genes G protein signaling 12(RGS12) related to the occurrence and development of OS affect the process of OS by regulating the proliferation of OS cells through YAP. For example, miR-375 and miR-624-5p enhance the proliferation, migration and invasion of OS cells and accelerate the progress of OS by enhancing YAP activity and the number of nuclear YAP, respectively [117, 118].RGS12 negatively regulates the transcription activity of YAP/TEAD1 complex through its PDZ domain function, thus inhibiting the metastasis of OS cells and delaying the development of OS [119].Similarly, it was found that the expression of TAZ in OS tissues and cell lines was also up-regulated. With the over-expression of TAZ, the oncogene miR-224 was up-regulated, thus inhibiting the expression of tumor suppressor SMAD4 and inducing the proliferation, migration and invasion of OS cells [120]. Interestingly, Shen et al. found that oncogene miR-135b and TAZ can form a positive feedback pathway to increase the transformation, migration and invasion of OS cells. TAZ is the direct target of miR-135b, which upregulates the expression of miR-135b, while miR-135b promotes the tumorigenic function of TAZ in vivo [121].

The expression of YAP/TAZ is positively correlated with the progress and grading of CS [122].At present, it has been proved that YAP is involved in regulating the proliferation, aging and invasion of CS cells. Nuclear YAP is necessary to obtain carcinogenic phenotype and CS growth. Compared with adjacent normal cartilage, YAP expression in CS tissue is up-regulated, which is positively correlated with CS grading score. YAP deletion inhibits CS cell proliferation and induces CS cell aging, which reduces the growth of xenograft tumors [122].The role of tumor suppressor genes and oncogenes in CS is also closely related to YAP. The deletion of tumor suppressor genes Trp53 and Rb1 in chondrocytes drives the migration and invasion of CS cells and tumor formation by promoting YAP expression and nuclear translocation [123]. Thioredoxin interacting protein (TXNIP) is also a tumor suppressor gene of CS. YAP, as an upstream molecule of TXNIP, negatively regulates the expression of TXNIP mRNA and protein, promotes the proliferation of CS cells and the progress of CS [124].Protein arginine methyltransferase 1(PRMT1) has been identified as an oncogene. PRMT1 acts on the upstream of LATS1, inhibiting the phosphorylation of YAP mediated by LATS1, leading to the increase of YAP nuclear accumulation, thus promoting the proliferation and survival of CS cells. PMRT1 was positively correlated with the expression of YAP, and was significantly correlated with high histological grade and poor prognosis [125].Therefore, inhibition of Hippo pathway activation or promotion of YAP/TAZ phosphorylation are viable targets for the treatment of OS and CS.

Osteoporosis

OP is a disease of bone loss, microstructure deterioration and brittle fracture [126]. On the one hand, the normal metabolism of bone tissue depends on the dynamic balance between OB bone formation and OC bone remodeling. On the other hand, the differentiation of MSC into adipogenesis and osteogenesis is a mutually exclusive process. When these two balances are broken, diseases such as OP may be caused [127, 128]. Hippo signaling pathway plays an important role in regulating the balance of bone formation and absorption, adipogenesis and osteogenesis, so it can regulate the occurrence and development of OP (Table 1; Fig. 5).YAP/TAZ deletion and acute YAP/TAZ-TEAD inhibition reduce the mRNA expression of osteogenic genes, such as osteocalcin (Ocn), alkaline phosphatase (Alp) and bone sialoprotein (Bsp), which damages bone accumulation and remodeling and leads to spontaneous fractures [129]. In OVX mouse model, it was found that YAP/TAZ expression can promote OB differentiation, inhibit bone loss and improve OP [130, 131].WNT is recognized as promoting bone symmetry metabolism and blocking OP pathway. And the up-regulation of YAP may be an important way for WNT to block OP. WNT promotes bone formation through YAP/BMP signal transduction during fracture healing [9].TAZ expression is down-regulated in OP, and TAZ global gene knockout promotes OC differentiation by up-regulating the NF-κB signal transduction induced by RANKL and the expression of nuclear factor AT1(NFATc1) mRNA and protein, which leads to low bone mass in OP [24]. Apart from balancing osteoblasts and osteoclasts, YAP/TAZ is also a key regulator to control the differentiation of MSC.Their expression upregulates Runx2 and downregulates PPARγ, which contributes to bone formation rather than fat formation [15, 132–134].A recent study shows that small molecule stimulation that activates TAZ leads to TAZ nuclear localization, induces OB differentiation and inhibits lipogenesis, which can protect OVX-induced bone loss in vivo [135].The above research shows that the expression of YAP/TAZ is helpful to maintain bone homeostasis and prevent OP, and it is expected to become a potential target of OP treatment intervention.

Osteoarthritis

OA is the most common degenerative joint disease, characterized by progressive degeneration of articular cartilage, subchondral bone thickening and osteophyte formation, and progressive destruction of articular cartilage is one of the main pathological manifestations [136].Cartilage is an avascular tissue composed of chondrocytes and ECM. The damage of chondrocytes and metabolic imbalance of ECM are closely related to the development of OA [60, 137].The existing research shows that the Hippo signaling pathway plays a key role in chondrocyte differentiation, proliferation, apoptosis and extracellular matrix homeostasis. However, the exact role of Hippo pathway in OA is still controversial in different studies (Table 1; Fig. 5). On the one hand, some studies believe that YAP is an important regulatory factor to promote OA. In mice and human OA models, it was found that the expression of YAP was up-regulated, and the levels of YAP mRAN and protein were higher than those of normal cartilage tissues [138].YAP overexpressed in OA tissue significantly inhibited the proliferation of chondrocytes, decreased the expression of differentiation-related genes such as Runx2, and promoted the apoptosis of chondrocytes. Inhibition of YAP can increase the proliferation and differentiation of chondrocytes, thus improving OA [68].In addition, YAP expression not only promoted the expression of catabolic genes in chondrocytes, but also inhibited the expression of anabolic genes, such as type II collagen α 1 (COL2A1) and Sox9, which eventually led to ECM decomposition and articular cartilage degeneration. Inhibition of YAP can reduce MMP expression and hinder the progress of OA [138].On the other hand, some research results are contrary to the above reports. Hao et al. found that the signal transduction of hippocampus in OA chondrocytes was overactivated [66].Deng et al. reported that the expression of YAP in OA cartilage decreased, and the expression level of YAP decreased with the severity of OA and OARSI grading [73].The mechanism of spontaneous OA caused by the deletion of hnRNPk, a member of heteroribonucleoprotein (hnrnp), is to induce the activation of Hippo signal and the decrease of YAP expression, and promote cartilage decomposition [139].Up-regulation of YAP expression can inhibit the expression of MMPs and ADAMTS, and increase the expression of type II collagen (Col -II) and aggrecan (ACAN), thus delaying the progress of OA [66, 73, 139].In addition, MSC aging is related to the maintenance of tissue homeostasis, which will lead to degenerative diseases such as OA related to aging [140].YAP cooperates with TEAD to activate the expression of forkhead box D1(FOXD1) ,a protective protein for the elderly. It is found that the lack of YAP leads to the down-regulation of FOXD1, while the over-expression of YAP or FOXD1 revives the aging MSC. YAP-FOXD1 is a potential target for gene therapy to alleviate osteoarthritis [141].The above report reveals that YAP/TAZ plays an important role in cartilage formation and cartilage homeostasis. We think that the expression of YAP/TAZ in cartilage should be kept at an appropriate level, and the high or low expression of YAP/TAZ may lead to OA, which may be the reason for the contradiction in existing research.

Intervertebral disc degeneration

IDD is a common degenerative disease of cartilage, and its pathogenesis is still unclear. The existing studies believe that it is closely related to the aging and apoptosis of nucleus pulposus cells(NPC)and the metabolic imbalance of ECM [142, 143]. Hippo pathway is closely related to NPC aging, apoptosis and ECM metabolism, which affects the progress of IDD, but the current research is controversial (Table 1; Fig. 6).

Fig. 6.

Hippo in RMS, IDD and Muscular dystrophy. (A) Hippo pathway in IDD: YAP plays a role in IDD by regulating NPC aging, apoptosis and ECM degradation, but the exact role is controversial. (B) Hippo pathway in RMS: the high expression of YAP/TAZ in ARMS tissue promotes the proliferation of cancer cells and reduces apoptosis; YAP also interferes with the expression of MYOD1 and MyoG, maintains ERMS differentiation arrest and cooperates with Ras to promote ERMS occurrence, while TAZ expression promotes ERMS cell proliferation and metastasis. (C) Hippo pathway in the Muscular dystrophy: YAP regulates the expression of protein decomposition factors Atrogin-1 and MuRF1 in skeletal muscle, thus affecting the decomposition of skeletal muscle protein, and finally regulating the occurrence and development of muscular atrophy, but the exact role needs to be studied

On the one hand, some studies reported that the expression of YAP/TAZ negatively regulated NPC aging, apoptosis and ECM degradation, which hindered the development of IDD. Aging NPC accumulates with age and intervertebral disc degeneration. Telomere-based p53-p21-pRB pathway has been proved to induce NPC aging [144].It has been found that compared with normal NPC, aging NPC is accompanied by more activation of Hippo pathway and phosphorylated YAP. Using lentivirus shYAP to inhibit YAP expression will increase the levels of p53 and p21 proteins, induce NPC to age, and thus lead to IDD [145].It is reported that the IDD-relieving drug Monoglucoside upregulates the expression of YAP/TAZ by inhibiting the phosphorylation of MST1/2 and LATS1/2, thus reducing the expression of p53 and p21 to inhibit the aging of NPC [146].The increase of RORα is related to the increase of apoptosis of nucleus pulposus (NP) cells. RORα inverse agonist SR3335 can prevent NPC apoptosis by inhibiting YAP phosphorylation, which has the potential to treat IDD [147]. Polymethylmethacrylate (PMMA) is the most common bone cement used in kyphoplasty, and the infiltration of bone cement into intervertebral disc usually causes problems. Ge et al. found that PMMA particles can promote NPC apoptosis and induce IVD degeneration by down-regulating YAP [148].The dynamic balance of ECM synthesis and catabolism is also an important condition to maintain the health of intervertebral disc. Up-regulation of YAP expression can significantly reduce the expression of MMP-13 and ADAMTS4 and increase the expression of COL2A1 and ACAN mRNA, thus weakening the decomposition of ECM in IDD model of rats and reversing the progress of IDD [147].In addition, the expression of fibronectin-containing type III domain 5 (FNDC5) of irisin from iris eggs in IDD decreased. Irisin increased the expression of (COL2A1 and ACAN) and inhibited MMPs and ADAMTSs by up-regulating YAP protein expression, thus promoting ECM synthesis [149].

On the other hand, some studies believe that YAP plays an important role in promoting the progress of IDD. It has been reported that the overexpression of YAP will lead to the decrease of the expression of Sox-9, Col -II and ACAN and the increase of MMP-13 level, thus accelerating the degradation of ECM. In contrast, VP, as a YAP inhibitor, has slowed down the development of IDD [150].In addition, β-catenin has been found to be up-regulated in IDD tissue, inducing apoptosis of NP cells, increasing the expression of matrix degrading enzymes and accelerating the development of IDD [151, 152].Chen et al. found that YAP can form a transcription complex with β-catenin and translocate into the nucleus, increase NPC apoptosis and ECM decomposition, and accelerate the progress of IDD [150].The above reports show that targeting the Hippo pathway is an effective strategy to treat IDD. We speculate that the contradiction of YAP/TAZ in IDD may be similar to that in OA, so the expression of YAP/TAZ in healthy intervertebral discs should also be in an appropriate range, and too high or too low may lead to IDD.

Muscle sarcoma and myasthenia gravis

RMS is a kind of mesenchymal cancer occurring in skeletal muscle tissue, which mainly occurs in children and young people. There are two subtypes of alveolar rhabdomyosarcoma (ARMS) and embryonic rhabdomyosarcoma (ERMS) [153, 154]. Hippo pathway regulates cell proliferation, invasion, senescence and myogenic differentiation of RMS cell lines, and then affects the occurrence of RMS (Table 1; Fig. 6).ARMS is an invasive skeletal muscle sarcoma, and the paired box-like tridentate box-like protein O1 (PAX3-FOXO1) fusion oncogene is the driving factor of ARMS [152, 155]. Ras-association domain family 4(RASSF4), the target gene of PAX3-FOXO1, is up-regulated in PAX3-FOXO1 positive ARMS cells and tumors, and inhibits the phosphorylation of YAP/TAZ by binding with MST1, thus promoting the growth, proliferation and escape from aging of ARMS cells [156].Similarly, in another study, it was found that the lack of Hippo signal transduction in the genetically engineered mouse model of ARMS led to the increase of proliferation, invasion, aging and differentiation of ARMS cell lines, which accelerated the occurrence of tumors [21]. Consistent with YAP, TAZ is also highly expressed in ARMS cells and tumors. In vitro, inhibition of TAZ can reduce the proliferation of ARMS cells, induce apoptosis and support myogenic differentiation. In vivo, inhibition of TAZ can weaken the growth of ARMS xenograft tumors [22].Though the carcinogenic driving factors of ERMS have not been completely determined, ERMS and other RMS subtypes have one thing in common. Although myogenic differentiation factor such as MyoD and MyoG are expressed, cells are locked in the state of proliferation into myocytes [157].The expression of YAP is up-regulated in ERMS, and YAP-TEAD1 is necessary to drive continuous proliferation. Moreover, YAP interferes with the expression of myogenic differentiation genes such as MyoD and MyoG, maintains the differentiation block of ERMS, and promotes the progress of ERMS [158]. Compared with YAP, the expression of TAZ does not inhibit myogenic differentiation, but active TAZ can drive the expression of oncogenes such as Myf5. The abundance of TAZ protein is related to the decrease of survival rate of ERMS, and knocking out TAZ can reduce the proliferation and metastasis of ERMS cells [23]. In addition, ERMS tumors usually have Ras mutation, so they can be called “Ras-driven rhabdomyosarcoma” [159, 160]. A study not only found that YAP expression supported the proliferation, survival, undifferentiated state and tumorigenesis of ERMS cell lines, but also showed that YAP alone was not enough to initiate and support tumorigenesis. The cooperation between YAP and Ras signals specifically initiated tumorigenesis in Ras-driven RMS model [161].Other signaling pathways, such as Hedgehog (Hh) and NOTCH, could also modulate YAP and regulate the occurrence and development of tumors. Activation of Hh could increase the expression of YAP, promoting the proliferation and progress of OS cells by up-regulating long-chain noncoding RNA H19 expression [162]. YAP and Notch pathway were highly expressed in ERMS, and they were highly correlated. A new interaction of Notch-YAP pathway promoted the proliferation of ERMS tumor cells and antagonized myogenic differentiation, which showed that activation of Notch pathway increased YAP expression, while inhibition of YAP decreased Notch signal transduction [163–165].These studies suggest that targeted therapy through the Hippo pathway may be beneficial to sarcomas.

The main cause of muscular atrophy is the imbalance of synthesis and degradation of protein, which is common in some pathological abnormal States, such as denervation, disuse, aging and catabolic diseases (such as diabetes and sepsis) [166, 167].YAP can regulate the synthesis and decomposition of protein in skeletal muscle, which is a reliable target for the treatment of muscular atrophy, but its exact role is still controversial. (Table 1; Fig. 6). Some studies report that YAP is a factor promoting muscle synthesis. For example, Goodman et al. reported that the overexpression of YAP may induce muscle hypertrophy and inhibit muscle atrophy by inhibiting the expression of myodystrophin, F-box (MAFbx)/Atrogin-1 and muscle ring finger 1 (MuRF1), thus inhibiting the degradation rate of protein [109].Watt et al. reported that YAP promoted protein synthesis through TEAD transcription factor, positively regulated the quality of basic skeletal muscle, and then promoted skeletal muscle fiber hypertrophy and alleviated neurogenic muscular atrophy [168]. MST1 kinase, the focal member of Hippo pathway, is up-regulated during muscular atrophy, and MST1 deficiency reduces FOXO3a-dependent transcription of Atrogin1 gene in muscular atrophy, thus effectively resisting muscular atrophy [169, 170]. However, it is uncertain whether the phosphorylation and activity of YAP are affected. In addition, the impaired YAP expression is involved in the mechanical sensing defect of myoblasts in LMNA gene-related congenital muscular dystrophy [171].On the other hand, it has also been found that the expression of YAP increases the mRNA expression of MuRF1 and Atrogin-1, which are key regulatory factors of muscle proteolysis and induce muscle atrophy significantly [172].We think that the controversy of Yap in the regulation of skeletal muscle quality may be due to the difference of induced YAP expression and treatment time, but there may also be other reasons, which deserve our in-depth study. In a word, these studies reveal that inhibiting Hippo pathway is a potential new mechanism for treating muscle atrophy.

Clinical application of Hippo-YAP/TAZ signaling pathway -related drugs

Hippo signal transduction disorder will lead to a variety of musculoskeletal diseases, so Hippo pathway is a feasible target for the treatment of musculoskeletal diseases. In recent years, YAP/TAZ has attracted people’s attention as a double-sided drug target. In recent years, it has been found that mechanical transduction can promote the proliferation, migration and chemotherapy resistance of cancer cells [173].The most noteworthy thing is that YAP/TAZ, the conducting medium of the Hippo pathway, which can respond and conduct mechanical signals, is often up-regulated in cancer [174].VP destroys the proliferation of RMS cells by inhibiting the expression of YAP/TAZ in ARMS and ERMS [26].We think it is necessary to continue to explore whether VP can alleviate the tumor by targeting YAP/TAZ to block mechanical conduction. Although there is no YAP/TAZ targeted drug to treat OP and muscle atrophy, some studies show that YAP/TAZ activator can be used as a promising therapeutic mechanism. OP is often related to the damage of mechanical conduction. Part of the mechanism of estrogen therapy for osteoporosis is to enhance the expression of YAP/TAZ, improve the sensitivity of bone cells to mechanical load and subsequent mechanical transduction of bone cells, and then promote bone formation and inhibit bone absorption [175].Inflammatory factors up-regulate the expression of Atrogin-1 and other muscle decomposition factors, which play an important role in the occurrence and development of muscular atrophy. TAZ activator IBS008738 can promote the transformation of muscle MP from M1 phenotype to M2 phenotype, and then up-regulate the expression of IL-1 and inhibit the expression of TNF-α and IL-6, thus saving muscle atrophy caused by inflammation in secondary brain injury [176].Unfortunately, the application of YAP/TAZ targeted drugs in the treatment of OA and IDD is controversial. The increase of ECM stiffness leads to cartilage degeneration and accelerates the progress of OA. Injection of VP in mouse OA model can overcome ECM sclerosis by inhibiting YAP, thus reducing chondrocyte apoptosis and abnormal formation of subchondral bone, and improving the development of OA [177]. YAP and β-catenin proteins are up-regulated in OA and IDD, and their interaction induces IDD to accelerate ECM degradation [150, 178]. As a YAP inhibitor, VP saved the IDD induced by YAP/β-catenin signaling. However, melatonin, as a potential therapeutic drug for IDD, inhibits the activation of NF-κB pathway induced by TNF -α by up-regulating YAP, thus inhibiting ECM catabolism [179].In a word, it is necessary to develop new drugs for musculoskeletal diseases by targeting HIPPO pathway, and the exact role of Hippo pathway in cartilage is worthy of our study, so as to help clarify the direction of developing Hippo-related drugs for cartilage diseases such as OA and IDD.

Conclusion and perspectives

In a word, recent studies show that Hippo pathway is the key signal pathway to regulate musculoskeletal diseases. In bone, YAP/TAZ can regulate Wnt, TGF-β, NF-κB and other bone-related pathways. In cartilage, YAP/TAZ regulates the proliferation and differentiation of chondrocytes and ECM metabolism. In skeletal muscle, it is not only closely related to the expression of MRFs, inflammatory reaction, proliferation and differentiation of SC and the formation of ECM, but also affects the synthesis and decomposition of protein in skeletal muscle. As a double-sided drug target, YAP/TAZ may pave the way for better treatment of musculoskeletal diseases such as OA, OP, IDD, muscular atrophy, bone tumor and RMS.In addition to musculoskeletal diseases, the exact role of Hippo-YAP/TAZ signaling pathway in heart diseases, respiratory diseases and gastrointestinal diseases has also been clearly clarified. To sum up, in-depth exploration of the intrinsic function of Hippo-YAP/TAZ signaling pathway is helpful to reveal the pathophysiological mechanism of the disease from a new angle and provide a new direction for the diagnosis and treatment of the disease.Although the function of Hippo in musculoskeletal has made great progress, many key problems still exist. The contradiction of Hippo pathway in cartilage homeostasis needs to be clarified urgently, which is helpful for the treatment of OA and IDD. In view of the significant functional overlap between YAP and TAZ, many genetic studies that only lack YAP or TAZ may not reveal the true function of the Hippo pathway, so it should be improved in future research. Besides VP, there is no direct inhibitor or activator of YAP/TAZ at present, which may be more beneficial to the treatment of musculoskeletal diseases. It is especially important to note that Hippo is not only closely related to the development of diseases, but also plays an important role in the normal growth of tissues. Therefore, it is necessary to avoid affecting the normal function of this pathway when developing drugs. These problems are definitely worthy of further study.

Author contributions

Conceptualization, supervision, and writing—review and editing, J.H.; conceptualization, writing—original draft preparation, and visualization, J.Z.; writing—original draft preparation, L.W., L.L., X.Z. and Y.Z.; supervision, project administration, funding acquisition, X.Z. and Q.L. All authors have read and agreed to the published version of the manuscript.

Funding

The study was supported by the National Natural Science Foundation of China (Grant No. 32371184), Liaoning Province Applied Basic Research Program (No. 2023JH2/101300072), The Science and Technology Innovation Program of the General Administration of Sport of China (No. 22KJCX040) and Shenyang Science and Technology Talent Special Project (No. RC230321). Basic scientific research project of higher education institutions of Liaoning Province (JYTZD2023131).

Data availability

Not applicable.

Declarations

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The authors give consent for publication. The authors declare that they have not use AI-generated work in this manuscript.

Conflict of interest

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.