The Role of Osteoclasts in Psoriatic Arthritis

Zhen-Zhen Wang and Hong-Sheng Wang,2,

1Jiangsu Key Laboratory of Molecular Biology for Skin Diseases and STIs, Hospital for Skin Diseases (Institute of Dermatology),Chinese Academy of Medical Sciences and Peking Union Medical College, Nanjing, Jiangsu 210042, China;2Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, China.

Abstract Psoriatic arthritis (PsA) is a chronic immune-mediated inflammatory disease related to psoriasis involving bone and cartilage.It is a heterogeneous disorder with a variety of clinical manifestations,which can include peripheral arthritis,axial spondylitis,enthesitis,skin and nail disease,dactylitis,uveitis,osteitis,inflammatory bowel disease.The distinctive feature of PsA is enthesitis.The characteristic bone erosion at the bone–pannus junction in PsA is mediated by osteoclasts, which are multinucleated giant cells derived from hematopoietic stem cells.Although the pathological mechanism of osteoclasts in PsA is mainly related to the destruction of the diseased joint,the exact pathogenesis of PsA is complex and the factors involved in initiation and termination of osteoclast need to be further explored.Much attention has been paid to the importance of osteoclast in psoriasis arthritis for decades.Based on the role of osteoclasts in PsA, our review discusses the formation and characteristics of multinucleated osteoclasts in PsA,summarizes current developments in osteoclast-related pathways in PsA including classical receptor activator of nuclear factor-κB-receptor activator of nuclear factor-κB ligand-osteoprotegerin pathway and immunomodulatory factors, as well as their advances and corresponding treatment.At present, the molecular and signal pathway that interacts with osteoclasts in the pathogenesis of PSA has not been fully elucidated,therefore more detailed studies are expected in the near future.

Keywords: osteoclast, psoriatic, arthritis, bone resorption

Introduction

Psoriasis arthropathica, also known as psoriatic arthritis(PsA), is a chronic immune-mediated arthritic disease associated with psoriasis.A recent meta-analysis showed that the prevalence of PsA among patients with psoriasis is approximately 20%.1In most cases,the psoriasis precedes joint disease by about 10years.PsA is an inflammatory joint disorder with diverse clinical manifestations and heterogeneous bone involvement characterized by peripheral arthritis, axial spondylitis, enthesitis, dactylitis,phalitis, uveitis, osteitis, and skin and nail disease.2-3The main feature of PsA is enthesitis, which is inflammation of the connective tissue between the bone and tendon.2Although the pathogenic mechanism underlying this unique bone remodeling process is still uncertain,ample evidence indicates that the involvement of many signaling pathways and interlinked factors are crucial in the interactions among synovial cells, osteoblasts, and osteoclasts in the development of PsA.Osteoclasts are the primary cells responsible for bone resorption and remodeling.With the searching terms of (“psoriatic arthritis” OR “psoriasis” OR “arthritis”) and “osteoclast”, we searched in PubMed for the literature from January 2010 to December, 2020, and summarized the formation and regulation of osteoclasts and their roles in the pathogenic mechanism of PsA.

Pathogenic mechanism of PsA

Inflammation of the synovial membrane and an increased angiogenesis are key pathological features of PsA and can facilitate immune cell migration from the peripheral blood into the inflamed joint.2The influx of immune cells,including dendritic cells, macrophages, innate lymphocytes, mucosal-associated invariant T cells, natural killer cells, and mast cells, can lead to production of a large number of proinflammatory mediators.These proinflammatory mediators interact with a variety of synovial resident cells such as chondrocytes, osteoblasts, osteoclasts, and fibroblasts.These events contribute to the transmission of their own inflammatory feedback loops,which can lead to the manifestations and sequelae of PsA.2,4PsA and rheumatoid arthritis have a similar process of osteoclast-mediated bone erosion: Under the stimulation of essential osteoclastogenic factors within the synovium, massive numbers of osteoclast precursors(OCPs) enter the diseased joint space and mature into bone-degrading cells, leading to rapid and pronounced formation of osteoclasts in inflamed joints.5

Ritchlinet al.6proposed an osteoclast bidirectional assault model to explain the destructive pathologic mechanism observed in many psoriatic joints.The model suggests that circulating OCPs enter the synovium and differentiate into osteoclasts under the induction of receptor activator of nuclear factor-κB ligand (RANKL) expressed by synoviocytes(outside-in mechanism).Meanwhile,OCPs traverse endothelial cells in the subchondral bone and form osteoclasts following RANKL stimulation from osteoblasts and stromal cells(inside-out mechanism).This bidirectional attack ultimately results in bone erosion and PsA.

Formation and characteristics of multinucleated osteoclasts in PsA

The balance between osteoclasts (cells that resorb bone)and osteoblasts (cells that form bone) maintains bone homeostasis.7Osteoclasts are prominently situated at the bone–pannus junction and in the cutting cones that traverse the subchondral bone in the psoriatic joint.6It has been proposed that pathological resorption is, at least in part, due to an increase in the number of OCPs.6Blood samples from patients with PsA, particularly those with bone erosions visible on plain radiographs,have markedly higher numbers of OCPs than healthy controls.6OCPs principally appear in bone marrow as early monocytemacrophages.They are then attracted to the bloodstream by chemokines and circulate there until they are attracted back to the bone marrow.Next, OCPs bind to the bone surface by bone remodeling units released at sites undergoing resorption, where they differentiate into osteoclasts.8-9Once adhered to the bone,the mononuclear OCP fuses with its sister cells, and the terminally differentiated polykaryon is formed,which can no longer replicate.10The fusing process only takes place at the periosteal and endosteal surfaces of cortical and trabecular bone.11These multinucleated giant cells then adhere to bone, induce actin ring formation, and secrete hydrochloric acid.This acidifies the resorptive microenvironment,dissolving the hydroxyapatite crystals and releasing proteolytic enzymes including cathepsin K and lysosomal protease,which degrade the exposed organic matrix.10-11The osteoclast then resorbs the underlying bone to a depth of about 50μm, detaches and disassembles its actin ring and ruffled membrane, and migrates to its next site of resorption.Figure 1 briefly illustrates the osteoclast’s bone resorptive cycle.

Figure 1. Role of osteoclasts in bone resorptive cycle.Once adhered to the bone, the mononuclear OCP fuses with its sister cells, and the terminally differentiated polykaryon is formed.These multinucleated giant cells then adhere to bone, induce actin ring formation, and secrete HCL.This acidifies the resorptive microenvironment,dissolving the hydroxyapatite crystals and releasing proteolytic enzymes including Cath K and lysosomal protease, which degrades the exposed organic matrix.The osteoclast then resorbs the underlying bone, detaches and disassembles its actin ring and ruffled membrane,and migrates to its next site of resorption.OCP:osteoclast precursor.Cath K:cathepsin K;HCL: hydrochloric acid.

As multinucleated giant cells,osteoclasts arise by fusion of myeloid hematopoietic precursors formed in the bone marrow and develop from the same monocyte lineage progenitor cells.8With respect to the precise source of osteoclasts, murine CX3CR1hiLy6CintF4/80+I-A+/I-E+macrophages (also known as arthritis-associated osteoclastogenic macrophages)have been identified as the OCPcontaining population in the inflamed synovium, constituting a subset distinct from conventional OCPs in homeostatic bone remodeling.12A recent study showed that Gα13, a RANKL-inducible G-protein, is highly expressed in multinucleated osteoclasts and has an important feedback inhibitory effect on controlling osteoclast actin ring formation and resorptive function.13Osteoclasts are the only cells with bone resorption activity in vivo and can thus mediate destructive joint diseases such as PsA and rheumatoid arthritis.A study using a mouse model of dermatitis showed that the administration of minodronate could significantly suppress osteoclasts and improve the deteriorated bone mineral density and the trabecular and cortical bone structure.14

Osteoclast-related pathways in PsA

Receptor activator of nuclear factor-κB-RANKLosteoprotegerin pathway

Macrophage-colony stimulating factor (M-CSF) and RANKL are two essential signals for osteoclast differentiation,and these two cytokines are primarily expressed by stromal cells and osteoblasts.9As a tumor necrosis factor(TNF) superfamily member, RANKL is expressed by osteoblastic and immune cells.Through RANKL binding ligand, the protein acts on the adaptor molecule TNF receptor-associated factor-6 and activates nuclear factorκB, leading to osteoclast formation.At the end of this pathway is nuclear factor of activated T cells,cytoplasmic 1.15In addition to M-CSF and RANKL, the immunoreceptor tyrosine-based activation motif that activates calcium signaling is also required for osteoclastogenesis.16Although RANKL is essential in the classical osteoclast formation pathway, one study showed that anti-RANKL antibody did not improve the bone mineral density or number of osteoclasts despite administration of a sufficient dose.14In addition,osteoclasts can form through a receptor activator of nuclear factor-κB (RANK)-independent pathway under inflammatory conditions.In one study, a combination of the inflammatory cytokines TNF-α and interleukin (IL)-6 successfully induced mouse osteoclast-like cells that had bone-resorptive activity.17Both RANKL-induced and TNF-α/IL-6–induced osteoclasts expressed markers of terminal differentiation,including Nfatc1, Itgb3, Atp6v0d2, Ctsk, Calcr, Acp5,Dc-stamp, and Slc4a2.18

Osteoprotegerin (OPG) produced by osteoblasts is a natural inhibitor of osteoclastogenesis, acting as a decoy receptor that prevents RANKL from binding to its receptor RANK.19OPG is situated on the bone surface under osteoclasts to avoid excessive resorption.Although the expression of RANKL is increased in PsA-affected joints,OPG is not increased;this indicates that the RANKL/OPG axis is unbalanced, which may promote osteoclastogenesis.6TNF-stimulated gene 6 protein (the product of TNF-stimulated gene 6),which is expressed by osteoclasts(and OCPs) in response to proinflammatory cytokines, is functionally synergistic with OPG to inhibit osteoclast activation.20

Regulation of immunity

Immunologic factors play a significant role in the pathology of joint inflammation in patients with PsA.The IL-23/IL-17 axis is crucial in both PsA and psoriasis.The IL-17-producing T helper cell (Th17) is the critical T-cell subset that connects T-cell activation with bone destruction in autoimmune arthritis,including PsA.The entheseal resident T-cells and Th17 cells, which express the IL-23 receptor,produce inflammatory cytokines such as IL-6, IL-17, and IL-22 driven by IL-23.21Th17 cells induce osteoclast formation and maturation by directly expressing RANKL and by inducing peripheral mesenchymal cells to produce RANKL.22IL-17A plays a central role in the induction of pathological bone loss through direct activation of OCPs.One study suggested that IL-17A has at least a dual effect in patients with PsA, meaning that IL-17A not only upregulates RANK on pre-osteoclasts,making them hypersensitive to the RANKL signal,but also increases serum RANKL in the circulation.23Moreover, IL-17 can induce the expression of matrix metalloproteinase, a disintegrin and metalloproteinase with thrombospondin motifs, and RANKL;promote synovial fibroblasts and macrophages to further produce inflammatory cytokines,such as IL-1β,IL-6,and TNF-α;and eventually lead to osteochondral destruction.21Osteoclasts can in turn present antigens to T cells,24secrete chemokines such as IL-8 and chemokine ligand 5(CCL5),25and recruit and suppress thein vitroT-cell response to proliferative stimuli.26Furthermore, the interaction between osteoclasts and Th17 cells is also affected by mesenchymal stem cells.As attractive immune modulators,human palatine tonsil-derived mesenchymal stem cells can constitutively produce OPG.Th17 cells alone are sufficient to enhance osteoclast differentiation and activation by expressing RANKL in coculture with the OCP cell line RAW264.7,whereas human palatine tonsil-derived mesenchymal stem cells efficiently inhibit osteoclastogenesis by reducing the interaction between Th17 cells and OCP cells by producing high quantities of OPG.27

Inflammatory cytokines and certain hormones are also important regulators in inducing osteoclast activation and thus promoting osteoclastogenesis.10Research has confirmed that inflammation is a trigger for enhanced osteoclast activity.28One study demonstrated that RANKL/M-CSF–stimulated peripheral blood monocytes in patients with PsA produced higher levels of proinflammatory cytokines such as TNF-α,IL-1b,IL-17,IL-23,IL-2, and RANTES as well as increased osteoclastogenic potential compared with peripheral blood monocytes of patients with psoriasis vulgaris and controls.29These proinflammatory factors such as IL-33, osteopontin, IL-17,and TNF-α enhanced osteoclastogenesisviaexpression of RANKL and/or in a RANKL-independent manner in patients with PsA.30Recent studies have shown that the use of cytokine inhibitors (TNF or IL-17 inhibitors)improves bone mineral density in patients with PsA,which further supports the concept of cytokine-mediated bone loss in PsA.31Both OPG and anti-TNF antibodies can inhibit osteoclast formation by reducing OCP frequency in patients with PsA.6Other anti-osteoclastogenic mediators include interferon-γ, IL-10, IL-4, and IL-13.Interferon-γ remarkably decreases RANKL and increases OPG expression in osteoclasts.30Chemokine signals play significant roles in the enhanced homing and differentiation of circulating OCPs.CCL2,CCL5,and C-X-C motif chemokine ligand 10 have similar osteoclastogenic effects among them,with CCL5 showing the most important chemotactic action on OCPs.32Some new molecules and signals are being studied with respect to their specific roles in bone remodeling, such as Plexin-B1/Sema4D and transforming growth factor-β1,although the mechanisms have yet to be clarified.33The above information on the formation and regulation of osteoclasts is summarized in Figure 2.

Figure 2. Osteoclast formation and regulation in psoriatic arthritis.The formation and regulation of osteoclasts involves the classical RANKRANKL-OPG pathway and immunomodulatory factors as well as emerging regulatory pathways and molecules.In the figure,the red solid line indicates inhibition,the green solid arrow indicates promotion,and the green dotted arrow indicates secretion or an intramolecular signal.PBMC:peripheral blood monocytes;TNF: tumor necrosis factor-α;IFN-γ: interferon;IL: interleukin;Th: T helper;OPG: osteoprotegerin;OCP:osteoclast precursor;ITAM:immune receptor tyrosine-based activation motif;RANK:receptor activator of nuclear factor-κB;RANKL:receptor activator of nuclear factor-κB ligand;NF-κB:nuclear factor-κB;TRAP:tartrate-resistant acid phosphatase;TRAF:TNF receptor related factor;Cath K: cathepsin K;M-CSF: Macrophage-colony stimulating factor;NFATc1: nuclear factor of activated T cells 1;RANTE: regulated upon activation normal T cell expressed.

Related signaling pathways and treatments

PsA is mediated and regulated through many signaling pathways.Many new discoveries about osteoclasts have been reported.Bone morphogenetic protein family mediators are increased in the sera and correlated with enthesitis in patients with PsA, suggesting that the bone morphogenetic protein pathway may be relevant for the OBs differentiation.34Many molecules and secretions also play a regulatory role: miRNA-146a-5p expression in peripheral CD14+monocytes in patients with PsA induces osteoclast activation and bone resorption35;psoriatic cutaneous inflammation promotes human monocyte differentiation into active osteoclasts, facilitating bone damage30;blood-derived exosomes in patients with PsA enhance the process of osteoclastogenesis36;and the expression of Fas ligand in peripheral blood of patients with PsA is increased and positively correlated with the number of osteoclasts.28Additionally, two hormones are known to be closely related to bone resorption: parathyroid hormone and calcitonin.The binding of calcitonin to its receptor can inhibit osteoclast activation.In contrast,parathyroid hormone induces increases in bone resorption, resulting in hypercalcemia.Several osteoclast-targeted therapies have been developed for patients with PsA.Bone remodeling is mediated by several signaling pathways, including the Janus kinase (JAK)/signal transducer and activator of transcription pathway.Clinical trials have shown that tofacitinib, a selective inhibitor of JAK1 and JAK3, is active in patients with rheumatoid arthritis and PSA and may help to limit systemic bone loss by inhibiting disordered osteoclast formation and thus reduce joint bone erosion.37Bisphosphonate inhibits osteoclastogenesis but has a risk of adverse effects such as osteonecrosis of the jaw.38Programmed cell death–ligand 1 promotes RANKL-induced osteoclastogenesis through c-Jun Nterminal kinase activation and CCL2 secretion, causing programmed cell death-1 blockade to inhibit osteoclast formation and murine bone cancer pain.39Further discoveries are expected in the near future.

Problems and prospects

Although many studies focusing on the formation and function of osteoclasts in PsA have made progress,several problems remain to be solved.Given the relationship between skin lesions and joint damage, whether PsA and psoriasis are two distinct entities or one disease remains controversial.The role of some cytokines is also disputed.1,25 (OH)2D3, an osteoclastogenic factor, can exert its effects by inducing RANKL expression in osteoclastogenesis-supporting cells.7Conversely, 1,25 (OH)2D3can also abrogate the capacity of osteoclastogenic potential and proinflammatory cytokine secretion from peripheral blood monocytes.29The direct effects of IL-33 and IL-17 on OCP formation are also inconsistent.On the one hand,IL-33 and IL-17 induce OCP differentiation and accelerate bone resorption.On the other hand,studies using murine models and RAW264.7 cells have demonstrated an antiosteoclastogenic action of both IL-17 and IL-33.The difference of the effects might be related to the IL-17 concentration.40The synovium is the site of active interaction between immune cells and osteocytes.The interaction between T cells and osteoclasts is a key issue in the field of bone immunology.Emerging evidence is showing that polyfunctional T cells are enriched in PsA synovial tissue and that this is strongly associated with the Disease Activity in Psoriatic Arthritis score and theex vivotherapeutic response.41These findings might imply that this particular T cell is related to the formation and function of osteoclasts, thus affecting their selective function in specific parts and causing entheseal abnormalities and further bone erosion.These problems indicate the need to study the role of osteoclasts in the pathogenesis of PsA.At present, many patients with PsA experience substantial suffering.Ongoing research of osteoclasts in patients with PsA can help to elucidate the pathways involved in bone resorption,leading to the development of new therapies.Therefore,more detailed studies need to be conducted.

Conclusions

Osteoclasts play an essential role in the pathogenesis of PsA.Development of bone erosion is critically dependent on osteoclasts,which are capable of resorbing the mineralized matrix.ough the pathological mechanism of osteoclasts in PsA is mainly related to the destruction of the diseased joint,the factors involved in initiation and termination need to be further explored.The formation and regulation of osteoclasts involves the classical RANK-RANKL-OPG pathway and immunomodulatory factors as well as emerging regulatory pathways and molecules.Correspondingly, many therapies have been developed based on the mechanisms and pathways of osteoclasts in PsA.

This review summarizes current developments of the formation and pathogenesis of osteoclasts in PsA.However, there are also some limitations: how does the role of osteoclast change from physiological bone resorption to pathological bone resorption then lead to imbalance of bone remodelling;what is the effect of osteoclast’s activity and function on psoriatic lesions;how to logically correlate the signaling pathways related to osteoclasts in PsA and then screen out possible biomarkers and more targeted drugs through these researches.

As the only cells with bone resorption activity, the importance of osteoclasts is self-evident.Despite the intensive research of osteoclasts to date, further studies are required to elucidate the details of their role in PsA.Improvements in our understanding of the pathogenesis and formation of osteoclasts in PsA will be helpful to establish effective biomarkers for diagnosis, identify related therapeutic targets, and to develop precise drugs for the treatment of PsA.More in-depth and detailed study of osteoclasts in PsA will help to shed light on the studies for osteoclasts in other related arthritis and skin diseases.

Source of funding

This work was supported by the Chinese Academy of Medical Science Innovation Fund for Medical Science(No.2016-I2M-1-005).