Synovium and Joint Biology

Qian Chen, PhD

Yun Gao, MD, PhD

Dr. Chen or an immediate family member has stock or stock options held in NanoDe Therapeutics Inc. and serves as a board member, owner, officer, or committee member of the Orthopaedic Research Society. Neither Dr. Gao nor any immediate family member has received anything of value from or has stock or stock options held in a commercial company or institution related directly or indirectly to the subject of this chapter.

INTRODUCTION

Joint is a multitissue organ that plays an important mechanical role in supporting daily life needs of a living human being. Synovium, a connective tissue that links various tissues in the joint, not only functions mechanically but also coordinates the chemical and biological micro-environment within the joint space. In this chapter, we describe major components of synovium and derived tissues, including synovial membrane, synovial cells, and synovial fluid. Their structure, function, and composition are described in detail at the molecular level. Furthermore, major synovial related diseases are presented including rheumatoid arthritis (RA), primary or aging associated osteoarthritis (OA), and secondary or posttraumatic osteoarthritis. Understanding the role synovium plays in the pathogenesis of these diseases is critical in developing clinical treatment, surgical and pharmacological, of these major joint diseases.

SYNOVIAL MEMBRANE

Synovium, also called the synovial membrane, is a specialized connective soft-tissue membrane that lines the inner surface of synovial joint capsules. Together with bone, articular cartilage, tendon, ligament, and fibrous capsule, it is an important component of the tissues that form an integrated joint. As such, it not only has its own specific functions but also interacts with other tissues in the joint both structurally and functionally.¹

The function of synovium is several-fold. Structurally, it seals the inner joint cavity by physically connecting with bone, articular cartilage, capsule, and ligaments. Functionally, it enables lubrication of the joint not only through retention of the synovial fluid in the joint cavity but also through synthesis of the major lubricant in the fluid including hyaluronan and lubricin (PRG4).² Synovium also plays a regulatory function in the joint. Unlike the avascular articular cartilage, the other inner joint cavity surface tissue, synovium is vascularized. Therefore, it serves as an important communication channel for transport of nutrients, debris and waste removal, immune modulation, and inflammation in the joint. These specialized functions are achieved by major cell types in synovial membrane, both resident and infiltrated. The malfunction of synovial membrane, synovial cells, and synovial fluid is directly involved in major bone and joint diseases including rheumatoid arthritis, aging-associated osteoarthritis (primary OA), posttraumatic osteoarthritis (PTOA, or secondary OA), and other inflammatory joint diseases.³ The functions of normal synovium and its diseased states are summarized in Figure 1.

FIGURE 1 Schematic diagram of normal synovium and synovial changes under pathological conditions of rheumatoid arthritis (RA) and osteoarthritis (OA). Left: In normal synovial membrane, there are two major types of cells: type A macrophage-like cells, which are responsible for cleaning up debris in synovial fluid through phagocytosis, and type B fibroblast-like synoviocytes (FLS), which are responsible for synthesizing and secreting extracellular matrix in synovial fluid including hyaluronan and lubricin; Right: A, In the synovial fluid of RA patients, the concentration of stromal cell-derived factor 1 (SDF-1), also known as C-X-C motif chemokine 12 (CXCL12), is highly upregulated. C-X-C chemokine receptor type 4 (CXCR-4), the receptor of SDF-1, is distributed in the superficial zone of articular cartilage. Interaction of synovial SDF-1 with CXCR4 in human articular chondrocytes results in secretion of matrix metalloproteinase (MMP)-1,3, 9, and 13 and ultimately the degeneration of cartilage matrix. B, Activated macrophages chemo-attract T cells via neovascularization through paracrine tumor necrosis factor (TNF)-α. Together with the infiltrated lymphocytes they secrete TNF-α, interleukin (IL)-1, and IL-6, major cytokines involved in RA pathogenesis. C, During OA pathogenesis, the major pro-inflammatory cytokines involved include IL-1, IL-6, and TNF-α. Note that while the major source of TNF-α derives from activated/infiltrated immune cells in the hyperplasic synovium and bone marrow, cartilage cells can synthesize therefore autocrine IL-1 and IL-6 under pro-inflammatory conditions.

SYNOVIAL CELLS

There are two major types of cells within the synovial membrane: type A macrophage-like cells and type B fibroblast-like synoviocytes (FLSs).⁴ Type A macrophage-like cells are derived from hematopoietic monocyte lineage and account for 25% of the residential cells in synovial membrane. They are located in the inner surface of the joint cavity, responsible for removing debris in synovial fluid through phagocytosis. Mitochondria are important for synovial macrophages to fulfill this energy-consuming task. Type B FLSs are derived from mesenchymal stem cells. They are responsible for synthesizing and secreting major extracellular matrix proteins in synovial fluid including hyaluronan and lubricin (PRG4). Together with other serum proteins, hyaluronan provides viscosity of the synovial fluid, whereas lubricin lubricates the joint surface. The endoplasmic reticulum of FLS is essential for synthesizing those matrix molecules in synovial fluid. In addition, the FLS possesses some mesenchymal stem cell properties and can be used as source cells for cartilage repair.

SYNOVIAL FLUID

The synovial fluid is a specialized fluid form of synovial extracellular matrix, which serves physical, chemical, and biological functions in the joint. Physically, the fluid mechanics influence viscosity, static pressure, shear stress, and streaming potentials of the synovial fluid. Alteration of these physical factors out of the normal physiological range may induce articular surface damage, cell death, and acceleration of wear-and-tear during aging. Chemically, synovial fluid facilitates continuous exchange of oxygen, carbon dioxide, and metabolites between blood and synovial fluid. Synovial fluid also readily diffuses into articular cartilage and other soft tissues in the joint. This is especially important because it is the major source of metabolic support for articular cartilage, which is not supplied by blood vessels because of its avascular nature. Biologically, it serves as a medium for the joint tissues with which it contacts. The synovial fluid contains cells, extracellular vesicles, proteins including extracellular matrix and fragments, cytokines, chemokines, and
growth factors.⁵ For example, under normal conditions, synovial fluid contain <100/mL of leukocytes in which majority are monocytes. These biological components of the synovial fluid are essential for communication and coordination among tissues in the joint, which are at different anatomic locations but share common contact with synovial fluid. Such biological factors can regulate tissue growth during development as well as tissue degeneration under inflammatory conditions.⁶^,⁷

Synovial fluid may also contain microparticles, which are endogenous crystals formed as a result of dysregulated metabolic processes. These particulates include monosodium urate crystals, which are associated with gout; calcium pyrophosphate crystals, which are associated with calcium pyrophosphate deposition disease (CPPD); and basic calcium phosphate (BCP) crystals, which are associated with osteoarthritis.⁸ These particulates contribute to synovial inflammation, cartilage destruction, and subchondral bone remodeling in these synovial related joint diseases.

SYNOVIAL RELATED JOINT DISEASES

Communication between synovium and structural tissues including cartilage, bone, capsule, and ligaments is important for maintaining normal joint physiology, but also contributes to several joint disease processes. For example, BCP crystals that contain hydroxyapatite have been detected in 70% of OA cases, which correlate with the extent of cartilage degradation and lesion severity. As a “danger signal,” they activate a number of joint cells including fibroblasts, macrophages, chondrocytes, and osteoclasts, which produce cartilage-degrading matrix proteinases and pro-inflammatory cytokine. Thus, it provides an intervention point for treatment of joint diseases through either physically removing or cleaning inflammation source tissues with arthroscopic surgery and joint replacement, or through blocking tissue inflammation and degeneration pathways with disease-modifying antirheumatic drugs pharmacologically. The major synovial related joint diseases are described as follows.

RHEUMATOID ARTHRITIS

An autoimmune disorder, rheumatoid arthritis is a chronic inflammatory disorder that causes joint stiffness, swelling, and pain, which ultimately results in bone erosion and joint deformity. During this pathological process, the interaction of synovium and bone and cartilage can be direct (physical) or indirect (biochemical). The direct interaction is through pannus, the hypertrophied synovium that covers, invades, and erodes contiguous cartilage and bone. Pannus tissue contains activated FLS and macrophage-like cells that release interleukin (IL)-1 and other inflammatory cytokines as well as collagenase that cause cartilage destruction and bone erosion.⁹ Invasion of vascularized pannus into articular cartilage also leads to matrix removal and blood vessel growth in otherwise avascular cartilage tissue, and ultimately results in joint tissue degeneration.¹⁰

Secreted by inflamed synovium, cytokines and chemokines in synovial fluid can also trigger tissue degeneration through interaction with receptors in articular cartilage and bone. For example, the concentration of stromal cell-derived factor 1 (SDF-1), also known as C-X-C motif chemokine 12 (CXCL12), is highly upregulated in the synovial fluid of RA patients and to a less extent in OA patients. CXCR4, the receptor of SDF-1, is distributed in the superficial zone of articular cartilage. Interaction of synovial SDF-1 with CXCR4 in human articular chondrocytes results in secretion of matrix metalloproteinase (MMP)-1, 3, 9, and 13 and degeneration of cartilage matrix.¹¹ Thus, suppression of such biochemical interaction of synovium and cartilage through blocking inflammatory cytokines and chemokines signaling can also be developed into an intervention strategy for RA and OA treatment.

Such intervention strategy can be either surgical or pharmacological. Surgical synovectomy eliminates the synovium, the source of inflammatory cytokine and chemokine. Synovectomy significantly reduces serum levels of SDF-1 as well as MMP-9 and MMP-13 and is effective in both inflammatory OA and RA patients.¹² Pharmacologically, small molecules of CXCR4 antagonist inhibit interaction of SDF-1 and CXCR4 and downstream MMPs activation.¹³ They have been used for intervention of RA, OA, and PTOA. Because the SDF-1/CXCR4/MMP axis is conserved in different types of cells, modulating this axis has been used not only for the treatment of arthritis but also for cancer metastasis and epiphysiodesis.¹⁴

Autoimmune activation in RA may involve both innate and adaptive immune system. RA synovial fluid appears turbid because of the presence of inflammatory cells, predominantly neutrophils. The volume is increased but the viscosity is decreased, resulting in a reduced ability to lubricate and protect the opposing cartilage surfaces, thus further increasing the susceptibility of cartilage to pannus attachment and matrix damage. Activated T cells and macrophages secrete tumor necrosis factor (TNF)-α, IL-1, and IL-6, which are major cytokines involved in RA pathogenesis. Antibodies to neutralize these cytokine pathways as well as small molecules to inhibit overactivation of immune cells are the first-line drugs for RA treatment.¹⁵

PRIMARY (AGING-ASSOCIATED) OSTEOARTHRITIS

Osteoarthritis (OA) is an aging-associated degenerative joint disease involving articular cartilage degradation, chronic inflammation, and bone remodeling.¹⁶ Although it is a leading cause of disability in the elderly, there is no FDA-approved disease-modifying osteoarthritis drugs (DMOADs) currently. The incomplete understanding of cell and molecular mechanisms triggering inflammation and degeneration in the joint during aging hampers the development of DMOADs that can target these processes. It has been shown that joint cells including articular chondrocytes, synovial cells, and mesenchymal stem cells undergo cell senescence, telomere shortening, and SASP (senescence associated secretory phenotype) manifestation during OA.¹⁷^,¹⁸^,¹⁹ Elimination of senescent cells in
the joint genetically or pharmacologically by so-called “senolytics” inhibits OA pathogenesis in mouse models.²⁰ These data suggest that senescent cells can be a key target for effective treatment of OA.²¹

Although OA is not considered as a classic inflammatory disease, synovial inflammation, or synovitis, is nevertheless correlated with OA progression.²² Synovium is mildly inflamed in early OA, which progresses in the middle phases with hypervascular changes in the synovium.²³ In late stages of OA, synovium exhibits thickening with hyperplastic cells, neo-vasculization, and villous formation. Excessively thickened synovium, filled with cells and fibrotic collagenous tissue, can physically restrict joint movement. Ultrasonography can be used to identify inflamed synovium. Pain is significantly correlated with synovial inflammation as well as bone marrow edema.²⁴

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