Bone Morphogenetic Protein signaling in joint homeostasis and disease

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Abstract

Despite advances in therapies that target inflammation and tissue destruction in chronic arthritis, stimulation of tissue repair and restoration of joint function, the ultimate goal of treatment, is far from achieved. We introduce a new paradigm that may help to improve our understanding and management of chronic arthritis. The presence or absence of tissue responses distinguishes destructive arthritis, steady-state arthritis and remodeling arthritis. Increasing evidence suggests that reactivation of embryonic molecular pathways is an important mechanism to stimulate postnatal tissue repair. Bone Morphogenetic Proteins (BMPs) have critical roles in skeletal development and joint morphogenesis, but also in postnatal joint homeostasis and joint tissue remodeling. Therefore, modulation of BMP signaling may be an attractive therapeutic target in chronic arthritis to restore homeostasis and function of synovial joints.

Introduction

The bones of the skeleton are connected by different types of joints [1]. Synarthroses are fibrous zones between the cranial bones. They prevent motion and frequently close at the end of growth. Amphiarthroses are typically present in the sacroiliac joints and the spine. They consist of fibrocartilage and allow for limited motion. Most joints in the body are diarthroses or synovial joints. They permit a wide range of precise movements. The synovial joint should be considered as a complex organ that is composed of different tissues: the articular cartilage, the underlying subchondral bone, the synovial membrane, the joint capsule, associated tendons and ligaments and eventually menisci (Fig. 1). Their balanced cooperation allows the individual to move. This function requires low-friction contact between the bony bearings, efficient lubrication of the contact surfaces and multidimensional stabilizing forces that prevent dislocation. The continuous strain carried by the synovial joints, requires an enduring homeostatic process in which the balance between anabolic and catabolic processes is tightly regulated.

Chronic joint diseases are a major health problem. Although these disorders seldom lead to direct mortality, the economic burden caused by progressive morbidity, loss of function and disability remains a challenge to our society [2]. The outcome and severity of diseases such as osteoarthritis (OA), rheumatoid arthritis (RA) and spondyloarthritis (SpA) is determined by the balance in the joint between destructive and homeostatic or reparative pathways (Fig. 2) [3]. Catabolic effectors include pro-inflammatory cytokines such as interleukin-1 (IL-1) and tumor necrosis factor-α (TNF-α), prostaglandins, tissue destructive enzymes such as matrix metalloproteinases (MMP) and cathepsins and cells such as osteoclasts. Systemic and local anabolic tissue responses include anti-inflammatory cytokines such as IL-10, IL-1 receptor antagonist, co-stimulatory regulator molecules such as CTLA4, tissue inhibitors of MMPs (TIMPs) but also growth and differentiation factors.

The final goal of treatment in all chronic diseases is not only the inhibition of excessive tissue destruction but also the restoration of homeostasis and eventually the stimulation of tissue repair. In arthritic disease in particular, modulation of inflammatory and destructive pathways may not be sufficient to achieve restoration of joint function. Increasing evidence suggests that molecular pathways important during development and growth are reactivated in homeostasis and repair [4], [5], [6]. From this point of view, embryonic molecular signaling molecules such as Bone Morphogenetic Proteins (BMPs) become relevant in the context of chronic arthritis not only to understand the complex pathophysiology of disease but also to develop regenerative therapeutic strategies.

The Bone Morphogenetic Proteins and closely related Growth and Differentiation Factors (GDFs) are a large group of structurally related polypeptides that belong to the transforming growth factor-β (TGF-β) superfamily [7], [8]. Within the BMP/GDF family, different groups can be further distinguished based on structural homology (Table 1) [7], [8], [9]. The original discovery of BMPs as protein factors that induce both ectopically and in vivo a cascade of endochondral bone formation [10], [11], [12], [13], has strongly stimulated the study of their function in skeletal development (for review, see [14], [15]) and joint morphogenesis [16], [17], [18], [19], [20]. However, it has become increasingly clear that BMPs are involved in a wide array of biological processes both during development and in postnatal life [21], [22]. These processes include the specification of the dorso-ventral body axis and the development, growth and homeostasis of most organs. BMPs can act as morphogens, growth factors or cytokines depending on their spatio-temporal expression and target cells. Their downstream effects include cell lineage determination, differentiation, motility, adhesion and death [22].

In their canonical pathway, homodimeric BMPs induce ligand-dependent type I and II receptor heterodimerization. These receptors are transmembrane serine–threonine kinases and phosphorylate intracellular receptor-smad signaling molecules (R-smad1/5) that bind common-smad4 (co-smad4) and then translocate to the nucleus [7], [9], [23] (Fig. 3). The diversity of cell responses to BMPs can at least partially be explained by differences in the affinities of distinct ligands for specific type I and II receptor combinations [7], [9], [24]. For instance, the BMP-receptor type Ia (BMP-RIa, also known as Activin-like kinase-3 (Alk-3)) can bind both BMP2/4 and BMP 6/7 in combination with either the BMP type II receptor, Activin type IIa receptor or Activin type IIb receptor [25], [26], [27]. BMP signaling is further regulated by extracellular antagonists such as noggin, chordin, gremlin, the DAN/Cerberus family, follistatin, follistatin-related protein and sclerostin (for review see [28]), by accessory receptors such as endoglin [29] and BAMBI [30] and by intracellular inhibitors such as inhibitory-smads (I-smad6/7) [31], [32]. Transcriptional responses to BMP signaling are tightly controlled by different co-activators and co-repressors (for review see [7], [24]). In addition, ligand and receptor availability is dependent on propeptide processing [33] and endocytic trafficking, respectively [34].

In this review, we introduce a new paradigm of arthritic disease with the focus on the balance of damage and repair. We further discuss and position the potential relevance of BMPs in this paradigm.

Section snippets

Joint homeostasis

The function of the synovial joint is to connect the elements of the skeleton and to allow motion. To achieve these goals, the joint is a well-organized organ in which different tissues interact to provide an agile structure with low-friction contact, lubrication of different surfaces and external and internal stabilization. A thin layer of articular cartilage is found at the edges of the skeletal bones. It belongs to the postnatal cartilaginous skeleton and is considered “stable”, in contrast

A new paradigm of joint diseases

Chronic joint diseases can be conceptualized from different angles. The clinician needs to diagnose, classify and treat specific disorders. The scientist wants to understand the mechanisms of disease looking at the target tissues, genetic and environmental factors, critical molecular signaling and specific features of the disease processes. It is the latter approach that should ultimately define our therapeutic strategies.

Three major forms of chronic joint disease are classified in clinical

BMPs and articular cartilage homeostasis and repair

The homeostasis of articular cartilage is critically dependent on the balance between anabolic and catabolic molecular pathways. Articular chondrocytes have a limited repair capacity after trauma [53]. Chondral lesions without injury to the subchondral bone do not heal spontaneously and gradually worsen. Osteochondral defects penetrate into the bone and show some attempts of repair with invasion of mesenchymal progenitor cells from the subchondral bone marrow cavities. However, no articular

Bone Morphogenetic Proteins and the synovium

The development of needle arthroscopy as a diagnostic tool in daily rheumatology practice, and the availability of biopsies at distinct stages of the disease, is rapidly increasing our knowledge of the pathology of arthritis and the molecular players involved. We have demonstrated that different BMPs, including BMP2, BMP6 and BMP7 are expressed in synovial biopsies obtained from patients with chronic arthritis [73]. Protein levels of BMP2 and BMP6 are significantly higher in patients with RA

BMPs and joint remodeling

Joint remodeling can be considered as a consequence of strain or damage. Anabolic efforts to preserve joint integrity may often appear unnoticed as they stay within the anatomical borders of the joint. However, in specific situations, metaplastic changes are occurring and new tissue formation becomes apparent. In OA, this process of osteophyte formation at the joint margins is often considered a defensive mechanism to increase joint stability. It seldom contributes to the symptoms. In SpA in

Conclusion and future directions

Stimulation of tissue repair and restoration of joint homeostasis and joint function is the ultimate goal of therapy in chronic arthritis. Endogenous anabolic molecular signaling pathways are activated in response to stress or injury. Depending on the nature and strength of the destructive forces, these endogenous mechanisms are to some extent capable of resisting the structural damage to the joint organ. In most cases however the balance is ultimately lost and progressive joint destruction and

Acknowledgements

The work of R. Lories and F.P. Luyten is supported by research grant 0.0390.3 from the Fund for Scientific Research Flanders. R. Lories is a post-doctoral fellow from the Fund for Scientific Research Flanders.

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