Abstract
Osteoarthritis (OA) is mainly caused by ageing, strain, trauma, and congenital joint abnormalities, resulting in articular cartilage degeneration. During the pathogenesis of OA, the changes in subchondral bone (SB) are not only secondary manifestations of OA, but also an active part of the disease, and are closely associated with the severity of OA. In different stages of OA, there were microstructural changes in SB. Osteocytes, osteoblasts, and osteoclasts in SB are important in the pathogenesis of OA. The signal transduction mechanism in SB is necessary to maintain the balance of a stable phenotype, extracellular matrix (ECM) synthesis, and bone remodelling between articular cartilage and SB. An imbalance in signal transduction can lead to reduced cartilage quality and SB thickening, which leads to the progression of OA. By understanding changes in SB in OA, researchers are exploring drugs that can regulate these changes, which will help to provide new ideas for the treatment of OA.
Cite this article: Bone Joint Res 2023;12(9):536–545.
Article focus
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This article reviews the role of cells and signal pathways in subchondral bone (SB) in osteoarthritis (OA).
Key messages
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The signal transduction mechanism in SB is critical to the balance between cartilage and SB.
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The imbalance of signal transduction in SB will promote the occurrence and development of OA.
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Understanding the signal transduction in SB is helpful in OA treatment.
Strengths and limitations
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Understanding the cells and signal transduction in SB is necessary for the stability of articular cartilage and the balance of bone remodelling, which is helpful when it comes to the exploration of the new pathogenesis of OA.
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The treatment of SB damage in OA greatly broadens the visual field of clinical treatment of OA.
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As all the studies included in this review are in English, the literature here may not be comprehensive enough.
Introduction
The development of osteoarthritis (OA) is mainly due to ageing, obesity, trauma, and congenital joint abnormalities that cause articular cartilage degeneration.1 OA mainly occurs in middle-aged and elderly individuals, especially in weight-bearing joints and joints associated with more activity (such as the knee joint, hip joint, cervical vertebra, and lumbar vertebra).2 Its clinical features mainly include chronic progressive joint pain, tenderness, stiffness, and limited movement.3 Genetic factors may include the inheritance of cartilage and subchondral bone (SB) and changes in gene expression patterns.4 Epidemiological studies have indicated that OA is mainly a mechanically induced disease, and many factors further affect its severity.5
Several tissues of the joint, including cartilage, the synovium, and subchondral bone, play key roles in the occurrence/progression of OA lesions.6 During the initiation/progression of OA, SB is the site of many dynamic morphological variations due to various cellular metabolic changes, which are part of the pathological process.7 SB and cartilage form the bone-cartilage unit, which participates in the pathophysiological process of OA at the mechanical level.8 Since the observable structural difference between articular cartilage and SB is important to the progression of OA, an increasing number of studies have focused on its participation and role in the pathological process of OA.9-11
During the pathogenesis of OA, cartilage and SB undergo catabolic and anabolic remodelling.12 This change in SB is not only a secondary manifestation of OA, but also an active part of OA, which is closely associated with the disease severity. Therefore, in this review, we discuss the communication between SB cells and various signal transduction mechanisms, and how their regulation promotes the progression of OA.
Changes in subchondral bone in OA
SB generally refers to the bone composition of the distal end of calcified cartilage, which can be divided into two parts: the subchondral bone plate (SBP) and the subchondral bone trabecula.13 The SBP is located below the calcified cartilage and is composed of a layer of cortical plate containing pores. The SBP is a layer of highly vascularized cortical bone located above the trabecular bone.14 The osteochondral plate is the exchange site for bone and cartilage, by which bone provides nutrients for cartilage. Some blood vessels and nerves enter the calcified cartilage through the pores in the SBP.15,16 The distribution and strength of these channels depend not only on age but also on the pressure transmitted by cartilage and subchondral bone in the joint, and shape and diameter vary with the thickness of the cortex.17 The subchondral trabecula, which is located in the lower part of the SBP, is a porous structure rich with blood vessels, which plays a key role in load absorption and cartilage nutrient supply.18-20 Subchondral cancellous bone has a non-homogeneous structure, which varies with the distance from the joint surface and has structural and mechanical anisotropy.21 SB dynamically adapts to mechanical force through coordinated bone remodelling.22 Bone resorption and the formation of osteoblasts are key factors in the bone remodelling process.23 SB responds quickly to mechanical load through bone remodelling and forms normal physiological conditions to adapt to joint movement.
In the different stages of OA, there are microstructural changes in SB (Figure 1). For example, Klose-Jensen et al24 observed enhanced SB turnover in early OA. In early OA, the SBP became thinner and porous, which was accompanied by subchondral trabecular deterioration and degeneration.25 Furthermore, blood vessels and nerves grow from SB to cartilage. In late OA, Botter et al26 found that calcified cartilage and SBP thickening occurred in severely eroded articular cartilage areas, while sclerosing subchondral trabeculae destruction resulted in bone cyst-like lesions. However, SBP thickening and modulation of bone from rod-like to plate-like structures does not depend on the severity of articular cartilage erosion.
Fig. 1
Subchondral bone (SB) in normal joints and osteoarthritis (OA). Normal knee joints include cartilage, synovium, and SB. SB also includes subchondral bone plate (SBP) and subchondral trabecula. In early OA, the SBP becomes thinner and porous. Cartilage and SB trabeculae deteriorated. At the same time, blood vessels and nerves grow from subchondral bone to cartilage. In late OA, calcified cartilage appears in the articular cartilage area and the SBP thickens. At the same time, subchondral trabecular sclerosis and progressive cartilage destruction lead to bone cyst-like lesions.
Cells in subchondral bone remodelling
Osteoclasts
Osteoclasts are formed by the differentiation of bone marrow myeloid progenitor cells and play an important role in bone resorption. In addition, these cells are closely related to bone metabolism.27 Relevant experimental results show that the activity level of osteoclast precursors is increased during periosteal vascular growth, and these cells invade the hypertrophic area of cartilage and then interact with the cells in it, resulting in significant changes in the morphology of the cartilage matrix and the formation of primary ossification centres.28,29 Relevant experimental results show that osteoclasts can degrade the osteochondral connection, which is mainly achieved in a matrix metalloproteinase (MMP)- and cysteine proteinase-dependent manner, leading to a certain reduction in bone density.30 Most mature osteoclasts appear on the bone surface and play a key role in bone remodelling. There are many factors that are closely related to bone metabolism in the bone matrix, including transforming growth factor beta-1 (TGF-β1). Insulin-like growth factor-1 (IGF-1) and the calcium phosphate complex can regulate bone metabolism, thus affecting the state of joints.31 Zhang et al’s research32 shows that under certain mechanical stimulation, TGF-β1 is expressed in osteoclasts. The expression level of TGF-β1 was significantly increased, and the expression level was increased when the intensity of stimulation increased. Comparative analysis showed that when chondrocytes are cultured with osteoclasts, the level of chondrocyte apoptosis was significantly increased. In addition, treatment with a TGF-β1 receptor (TGF-β1R) inhibitor could reverse chondrocyte apoptosis and reduce cartilage degeneration in rat OA.32 These studies have shown that TGF-β1 in SB can be transferred to the cartilage layer, which has an adverse effect on chondrocytes. IGF-1 is a protective factor in the synthesis and metabolism of chondrocytes. IGF-1 promotes collagen type II alpha 1 (Col II-α1) expression and inhibits MMP-13 expression by activating the PI3K/Akt and extracellular signal-regulated kinase (ERK1)/2 pathways (Figure 2).33 Moreover, insulin-like growth factor-1 (IGF-1) signalling can inhibit chondrocyte apoptosis by decreasing caspase-3 activity.34 In addition, various cytokines released by chondrocytes have certain effects on osteoclasts. Changes in the biomechanical properties of joints reduce the expression of interleukin 1 beta (IL-1β) in primary chondrocytes.35 IL-1β upregulates the expression of receptor activator of nuclear factor kappa-Β ligand (RANKL) in osteoblasts, causes osteoclast formation, and induces the formation of multinucleated osteoclasts (Figure 2).36 High expression of tumour necrosis factor-α (TNF-α) and IL-6 in OA chondrocytes was detected in an OA model.37 TNF-α leads to osteoclast differentiation by activating nuclear factor kappa B (NF-κB) in a RANKL-independent manner.38 In addition, TNF-α can indirectly induce osteoclast formation by stimulating osteoblast expression of RANKL.39 IL-6 indirectly induces osteoclast formation by activating the signalling factor gp130.40 Furthermore, hypertrophic chondrocytes are associated with senescent chondrocytes and can produce catabolic enzymes and chemokines (collectively referred to as ageing-related secretory phenotypes) to adjust the behaviour of subchondral osteoclasts.41,42
Fig. 2
The role of osteoclasts in subchondral bone in osteoarthritis (OA). Mature osteoclasts attach to the bone surface and dissolve bone during bone remodelling. After osteolysis, various factors including transforming growth factor beta-1 (TGF-β1), insulin-like growth factor (IGF)-1, and calcium phosphate complex are released from the bone matrix. Osteoclasts degrade articular cartilage in a matrix metalloproteinase (MMP)-dependent and cysteine protease-dependent manner. IGF-1 promotes the expression of colagen type II alpha 1 (Col II α1) and inhibits the expression and enzyme activity of MMP-13 by activating phosphatidylinositol 3 kinase (PI3K)/Akt and ERK1/2 pathways in rat endplate chondrocytes. In addition, IGF-1 signal protects chondrocytes from apoptosis by reducing caspase-3 activity. Interleukin 1 beta (IL-1β), released by chondrocytes, upregulates the expression of receptor activator of nuclear factor kappa-Β ligand (RANKL) in osteoblasts and indirectly induces osteoclast formation.
Osteoblasts
Osteoblasts differentiate from mesenchymal cells and promote bone formation.43,44 In OA, the activity of osteoblasts in SB is changed. Compared with normal osteoblasts, OA subchondral osteoblasts have increased levels of alkaline phosphatase activity, RANKL, osteocalcin (OCN), TGF-β1, IGF-1, and vascular endothelial growth factor (VEGF) release.45-47 VEGF release was also shown to be driven by hypoxia in primary human OA osteoblasts, which indicates that the release of VEGF may not be just a characteristic manifestation of OA subchondral osteoblasts.48 This increase in biological factors may lead to sclerosis, osteoclast formation, and angiogenesis.49,50 There is growing evidence that the formation of unmineralized immature new bone may cause osteoids in SB (cortical plate level and trabecular bone level), which has an adverse effect on tissue properties.51 For example, in OA-hardened subchondral cortical plates and bone trabeculae, osteoblasts have decreased mineralization abilities, which may be related to increased osteoblast production of type I collagen (Col I).52 Chan et al53 found that one of the molecular mechanisms for the decrease in SB mineralization ability was the increased expression of TGF-β in human OA subchondral osteoblasts, which may induce the expression of the mineralization inhibitor dickkopf-2 (DKK2). In addition, a significant decrease in some mineralized proteins in osteoblasts in sclerosing SB may lead to increased bone remodelling or abnormal bone matrix mineralization.54 In addition, ECM is secreted by osteoblasts and has some effects on bone mineralization. For example, calcium, phosphate, magnesium ions, and TGF-β1 stored in ECM can regulate bone homeostasis during bone remodelling.55,56
Osteocytes
Osteocytes are cells in the mineralized bone matrix, accounting for 90% to 95% of all cells in adult bones; they play an important multifunctional role in regulating bone homeostasis.57 In a recent genome-wide association study on osteocytes, new candidate loci related to OA were identified, suggesting that the expression of these genes in osteocytes may contribute to SB remodelling, which is important in the pathogenesis of OA.58 Subchondral osteosclerosis is the main pathophysiological manifestation of advanced OA and can disrupt cartilage homeostasis in patients with OA.59 Increases in bone mass, mineral density, and subchondral osteosclerosis have been reported in patients with OA, which may be due to a combination of repetitive microinjuries/fractures caused by mechanical load imbalance.60 The hardened SB has several structural features, including increased bone volume and density, a thickened SB plate, increased trabecular thickness, and reduced trabecular separation.7 Jaiprakash et al61 found that these SB variations in OA were associated with the level of osteocyte markers. There was a decrease in sclerostin (SOST) and an increase in DMP1 expression in OA samples. Up until now, many scholars have studied the physiological effects of SOST.62,63 For example, many scholars have shown that the loss of SOST expression can enhance osteogenesis (Figure 3).62,64 Conversely, mice overexpressing SOST exhibit overall suppressed bone formation, resulting in notable reductions of bone mass and volume.65-67 Mice overexpressing a transgene in which SOST is driven by the entire human SOST promoter (bacterial artificial chromosome (BAC)-SOST mice) also displayed reduced cancellous bone of the axial and appendicular skeleton due to reductions in bone formation.67,68 In addition, some studies have shown that SOST reaches the bone surface through the lacunocanalicular network, where it inhibits classic Wnt/β-catenin (cWnt) signal transduction in osteoblasts, which is related to the regulation of bone mass.69-71 Therefore, a decrease in the expression of SOST in OA osteocytes may be the reason for the increase in SB mass in OA. Contrary to the SOST level, an increased level of dentin matrix acidic phosphoprotein (DMP1) can lead to mineralization disorders and significantly delay osteoblast differentiation.72 Therefore, the abnormal mineral metabolism in SB in OA may be related to high expression of DMP1 in these osteocytes.73 In vivo results indicate that DMP1 is actively involved in bone dynamic balance, and mechanical loading can stimulate osteocytes to express DMP1.74-76 The increased level of DMP1 in subchondral osteocytes in OA is harmful to the normal mineralization process of SB in OA, resulting in an increase in osteoid volume and irregular bone mineralization. Jaiprakash et al61 observed that osteocytes (OA osteocyte phenotype) in OA SB were more round, rougher, and not arranged in any specific direction, but normal osteocytes showed uniformly arranged osteocytes. These results suggest that the irregular shape of osteocytes can promote OA, which may change the ability of bone to perceive mechanical stimuli, resulting in variations in mineral density.77,78
Fig. 3
The role of osteocytes in subchondral bone in osteoarthritis (OA). In OA, the expression of sclerostin (SOST) in subchondral bone decreased, while the expression of dentin matrix protein-1 (DMP1) increased. SOST reached the bone surface through the lacunocanalicular network, where it inhibits the classical Wnt/β-catenin signal transduction of osteoblasts and regulates bone mass. The increased expression of DMP1 can lead to mineralization disorder and significantly delay osteoblast differentiation.
Osteocytes secrete not only SOST and DMP1, but also TGF-β1, RANKL, and TNF-α to regulate bone homeostasis in subchondral bone, thus affecting OA. For example, Dai et al79 found that the TGF-β signal was activated in SB underneath the partial and full defect cartilage. Moreover, it has been found that loading can cause an increase in the anabolism of cortical bone, and that its mechanism is associated with the inhibition of the TGF-β-smad2/3 pathway in osteocytes.80 Osteocytes are the main producers of RANKL.81,82 Osteocyte apoptosis may indirectly stimulate osteoclastogenesis by inducing stromal/osteoblastic cells to secrete RANKL.82 In addition, RANKL secreted by osteocytes can induce osteoclast recruitment and differentiation to regulate chondrocytes indirectly.83 A previous study showed that osteocytes express tumour necrosis factor receptor 1 (TNFR1) and TNFR2, and TNF-α enhances RANKL expression in osteocytes directly and induces osteoclast formation both in vitro and in vivo.84
Signalling pathways in subchondral bone remodelling
Signal transduction mechanisms in subchondral bone are necessary to maintain the balance between a stable phenotype, ECM synthesis, and bone remodelling in articular cartilage and SB.85 An imbalance in signal transduction can lead to reduced cartilage quality and SB thickening, which leads to the progression of OA.86
WNT signalling pathway
WNT is an extracellular glycoprotein whose signal transduction involves different Wnt receptors that regulate β-catenin-dependent and noncanonical β-catenin-dependent pathways.87 It has been reported that WNT signal transduction is a key factor in cartilage, bone, and joint development.88 Moreover, the WNT pathway is important in bone pattern shaping.89 Typical WNT signal transduction is necessary to maintain mature articular cartilage, which is characterized by prolonged cell survival and no hypertrophic differentiation.90 In addition to cartilage formation, WNT signal transduction is important for bone development. High levels of WNT signal transduction can induce osteosclerosis.91 Wnt signalling is activated by reducing the Wnt antagonist β-catenin, resulting in bone formation and in thicker and harder bone.90,92,93 Wu et al94 evaluated the effect of Wnt inhibitors on OA in subchondral osteoblasts. Quantitative real-time polymerase chain reaction (qRT‒PCR) analysis of β-catenin and transcription factor 4 (TCF-4) showed that their levels increased in the late stages of OA, while the level of sclerosin was lower than that in early OA samples. In osteoblasts, lower expression of the Wnt agonist R-spondin-2 gene was related to the increase in sclerosin levels.64,95 In addition, osteocytes communicate through Wnt signals and play a role in synthesis and metabolism through osteoblast-mediated osteogenesis.96-99 DKK-1-mediated Wnt signal inactivation downregulates VEGF expression, resulting in reduced SB growth, osteoblast inactivation, and osteophyte formation.100 As a non-classical activator of the Wnt pathway, Wnt5a expression is increased fivefold in OA osteoblasts.101 Additionally, in bone remodelling in SB, osteoblasts and osteoclasts, which are the main cells associated with bone remodelling, are regulated by Wnt5a.102 For example, poor bone quality and formation were observed in Wnt5a-knockout mice.103 Compared with normal osteoblasts, osteoblasts harvested from OA joints showed irregular Wnt5a ligand expression, increased alkaline phosphatase (ALP) activity, and OCN release. Inhibiting Wnt5a expression could correct the abnormal ALP activity of OA osteoblasts to some extent.101 This evidence suggests that Wnt5a signal transduction may cause an imbalance in osteoblasts and osteoclasts, which increases SB remodelling and participates in excessive mineralization and formation.
TGF-β/BMP signalling pathway
The TGF-β superfamily includes approximately 40 members, such as TGF-β, nodal proteins, activin, and bone morphogenetic protein (BMP).104 TGF-β/BMP is important in bone formation and has a variety of functions in vivo.105 Zhen et al56 found higher levels of TGF-β in the SB of OA mice and human knee OA models than in healthy controls. The increased expression of TGF-β in SB caused OA-like symptoms in rats: a reduced level of proteoglycan, increased fractions and numbers of blood vessels in SBP, and increased bone mesenchymal stem cells in SB marrow, which promoted new bone formation in SB.56 Inhibiting TGF-β1 restored the microstructure of SB by preventing angiogenesis, reducing the number of MSCs undergoing osteogenesis, reducing proteoglycan loss, and increasing bone calcification.56 In OA, the SBP was significantly thicker than that in healthy subjects. The coordinated regulation of sclerosin and SBP is important in joint homeostasis.106,107 Because the expression of sclerosin is induced by TGF-β,80,108 and suppressed in the presence of load,109 TGF-β is important in regulating the thickness of the SBP. A previous study showed that canonical activation of WNT signals can induce WNT1-inducible-signalling pathway protein 1 (WISP-1) secretion in human OA cartilage.110 WISP-1 has been shown to have osteogenic effects by promoting osteoblast differentiation.111 As observed in OA, the secretion of WISP-1 may exert osteogenic effects on SB. In addition, WISP-1 can regulate TGF-β signal transduction by inhibiting Smad2.111 Therefore, the interaction between TGF-β and the WISP-1 signalling pathway may directly determine the response of cartilage and SB in OA.
MAPK signalling pathway
Mitogen-activated protein kinases (MAPKs) are a group of serine/threonine kinases that are present in all eukaryotes and respond to multiple stimuli. The MAPK family includes three major kinases: ERK, JNK, and p38 kinase (Figure 4).112 In bone biology, MAPKs have been shown to play important roles in adjusting bone mass by controlling the differentiation of osteoblasts and osteoclasts.113,114 ERK, p38, and JNK can accelerate osteoclast differentiation by altering activating protein 1 (AP-1), a key mediator of osteoclast formation. ERK signal transduction mediates the different stages of osteoblast differentiation by phosphorylating key transcription factors (such as runt-related transcription factor 2 (RUNX2)) and activating transcription factor 4 (ATF4).115 Similarly, p38 signal transduction promotes osteoblast differentiation based on the phosphorylation of distal-less homeobox 5 (DLX5) and RUNX2.116 Recently, the MAPK family was thought to be related to the pathophysiology of OA. Mechanical strain induction can produce MMP-13 via the activation of ERK in osteoblasts.117 In response to mechanical strain, osteoblasts in subchondral bone begin to produce MMP-13, which can stimulate cartilage degeneration. Moreover, OA articular chondrocytes have a significant effect on subchondral osteoblasts, and this effect is mainly mediated by ERK activation.118 An experimental study showed that OA subchondral osteoblasts have a certain regulatory effect on p38 signal activity in articular cartilage, and can regulate the expression levels of proliferative genes. This regulatory effect is mainly mediated by ERK signalling.119 The abnormal secretion of ADAMTS and MMPs in joints plays a key role in the early progression of OA. The upregulation of ADAMTS and MMPs is mediated by the activated ERK pathway in corresponding cells. In affected articular chondrocytes, the overexpression of MMPs in the coculture system could be reversed by inhibiting the ERK signal pathway with PD98059.119 Moreover, soluble factors released from SB mediate the release of MMPs in normal SB by activating the ERK signalling pathway.120 Activation of protease-activated receptor (PAR-2) in OA chondrocytes and cartilage can affect SB resorption by enhancing the levels of MMP-1, MMP-9, and IL-6.121 Its effect is mediated by ERK and p38 signalling activity, and adjusting the level of PAR-2 can alleviate the symptoms of OA, which suggests a promising target for OA therapy.
Fig. 4
Mitogen-activated protein kinase (MAPK) signal pathway in subchondral bone. The MAPK family consists of three kinases: extracellular signal-regulated kinase (ERK), stress-activated protein kinase/c-Jun N-terminal kinase (JNK), and p38 kinase. ERK signal transduction mediates the early and late differentiation of osteoblasts by phosphorylating key transcription factors (such as runt-related transcription factor 2 (RUNX2)) and activating transcription factor 4 (ATF4). Moreover, p38 signal transduction can also promote osteoblast differentiation through phosphorylation of distal-less homeo box 5 (DLX5), Osterix, and RUNX2. ERK, p38, and JNK all promote osteoclast differentiation by regulating activating protein 1 (AP-1) as a key medium for osteoclast formation. In addition, the upregulation of a disintegrin-like and metalloproteinase with thrombospondin (ADAMTS) and matrix metalloproteinases (MMPs) mediated by the activation of ERK signalling pathway plays an important role in the early development of osteoarthritis.
Treatments for the changes in subchondral bone in OA
In addition to well-known conventional drugs for OA therapy,122,123 some drugs that regulate changes in SB have recently become the focus of researchers.124 For example, the efficacy of anti-reabsorption agents in OA therapy has been assessed by restoring abnormal SB remodelling. Some scholars have found that bisphosphonates may play a key role in OA mainly through their role in SB.125 Patients with significant cartilage loss retained vertical trabecular structure after treatment with risedronate (RIS).126 However, at present, clinical researchers have not recommended bisphosphate as a drug for the treatment of OA.127 In addition, there is no unified standard for the dose and administration mode of bisphosphate in the treatment of OA. Therefore, whether bisphosphate should be used as a drug for the treatment of OA needs further evaluation. In animal models, there are other inhibitors of bone absorption (cathepsin K inhibitor and strontium ranelate) that may protect SB and cartilage, and can be used as clinical drugs for OA therapy.128-130
Increased osteoclast activity leads to excessive activation of TGF-β1 signalling in SB, and so subchondral TGF-β1 may be a therapeutic target for OA.56 In addition, blocking H-type angiogenesis in an animal model of OA could inhibit cartilage destruction and SB loss.131 For instance, bevacizumab (a vascular endothelial growth factor blocking antibody) can reduce subchondral H-vessel formation levels in OA models and delay the progression of OA.132 In addition to drug-mediated inhibition of VEGF, factors secreted by osteoclasts or osteoblasts in the SB microenvironment of OA, such as TGF-β1, platelet-derived growth factor-BB, and sLIT3, can exert positive effects on subchondral angiogenesis. Therefore, antagonists of these molecules may be potential drugs for the treatment of OA.133 For instance, Cui et al133 found that halofuginone alleviates OA by inhibiting the activity of TGF-β and H-type angiogenesis in SB. In addition, baicalein alleviates OA by protecting SB and inhibiting angiogenesis and synovial proliferation.134 Dihydroartemisinin reduces the inhibitory effect of scleroprotein by reducing leukaemia inhibitory factor secretion by osteoclasts, thus reducing abnormal bone remodelling, inhibiting SB angiogenesis, and further slowing the progression of OA.135 Production of nerve growth factor (NGF) by osteoclast precursors is a key driver of subchondral innervation during the development of OA.136 There is evidence that the small molecular coupling of the TGF-β receptor inhibitor TLY-2109761 can significantly reduce the excessive production of prostaglandin E2 (PGE2) by osteoblasts and relieve pain in OA mice by restoring abnormal bone remodelling.137 Moreover, diacetate and emodin may regulate the abnormal metabolism of subchondral osteoblasts in OA by increasing the level of β-catenin in subchondral osteoblasts by reducing DKK-1 and DKK-2 levels, which has a positive effect on the abnormal Wnt system in OA.138 Some scholars have reported the positive effects of resveratrol on osteoblasts in OA SB by inhibiting the cWnt pathway. Abed et al46 noted that resveratrol could promote the expression of β-catenin in SB and may activate cWnt signal transduction, which may play a beneficial role in SB changes in OA.
In conclusion, SB changes are an important part of the occurrence and development of OA. Cells and signal transduction in SB are necessary for the stability of articular cartilage and SB, and for the balance of bone remodelling. There is clear evidence that OA induces changes in bone homeostasis of the SB, tipping it to an increase in bone remodelling that results in osteosclerosis and some bone lesions. This change in bone homeostasis can in turn lead to a worsening of the disease by further inducing cartilage damage, inflammation, pain, etc. Thus, controlling SB homeostasis could be a possible target in OA.
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Author contributions
P. Luo: Conceptualization, Methodology, Investigation, Formal analysis, Data curation, Writing – original draft, Writing – review & editing.
Q. Yuan: Project administration, Investigation, Formal analysis, Data curation, Writing – original draft, Writing – review & editing.
M. Yang: Project administration, Resources, Writing – review & editing.
X. Wan: Resources, Writing – review & editing.
P. Xu: Conceptualization, Methodology.
Funding statement
The authors disclose receipt of the following financial or material support for the research, authorship, and/or publication of this article: this work was supported by the National Natural Science Foundation of China (82072432).
ICMJE COI statement
None.
Data sharing
The data that support the findings for this study are available to other researchers from the corresponding author upon reasonable request.
Open access funding
The open access fee for this article was self-funded.
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