Keywords

FormalPara Key Points

  • Osteoarthritis; Osteoarthritis (OA) is characterized degeneration of cartilage associated with global deteriorations in the joint.

  • Molecular mechanisms; Molecular mechanisms for development of OA have been examined using animal models and human chondrocytes, leading to identification of some causative factors.

  • Pathological conditions; Pathological conditions of OA is characterized by decreased anabolic activity and increased catabolic factors in the whole joint.

  • Joint homeostasis; Joint homeostasis is an entire environment of joint that is necessary for maintaining the joint in a healthy condition.

  • DMOADs; DMOADs is disease modifying osteoarthritis drugs that slow down the progression of OA or prevent OA.

1 Introduction

1.1 Osteoarthritis and Joint Homeostasis

Osteoarthritis (OA) increases during aging in association with degeneration of articular cartilage. Although OA is an aging-associated joint disease, OA is also caused or accelerated by trauma and joint injuries. Characteristic features of OA are degeneration of articular cartilage and break down of articular cartilage in association with subchondral bone changes and increased inflammatory reactions in synovium and cartilage. Joint homeostasis is balanced between anabolic factors and catabolic factors. Increased catabolic activity over anabolic activities is observed during development of OA. Although new surgical techniques and biomaterials to treat cartilage defects and osteoarthritic joints have been developed, overall clinical outcomes of the application of the solo technique were moderate mostly in a short-time period. Filardo et al. reported the clinical outcomes of autologous chondrocyte implantation (ACI) in patients with isolated degenerative cartilage lesions. Although the ACI procedure significantly improved symptoms, the overall results were lower with respect to the outcome reported in different study populations and the number of failures was higher [1]. Therefore, treating patients with degenerative cartilage is more challenging than patients with non-degenerative cartilage. Interestingly the efficacy of cartilage repair by periosteum transplantation was examined in a goat cartilage defect model with different surgical timing points. The early-treated group showed a better repair than the late-treated group [2]. This study suggests that degenerating cartilage has lower reparative capacity or the entire environment of damaged joint is less favorable for cartilage repair and restoring “joint homeostasis” is important. How joint homeostasis after a defect relates to joint homeostasis in the process of (idiopathic) OA is unknown. Therefore to understand the molecular mechanisms of OA is an essential step to treat joints with OA and to obtain better clinical outcomes after cartilage repair procedures. In this chapter, OA pathology and therapeutic approaches for OA are described.

2 Pathological Conditions in OA

2.1 Inflammation and Cytokines

Inflammation of OA is characterized by inflammation in synovium and increased inflammatory responses in cartilage [3]. A variety of inflammatory cytokines are produced by synovium and chondrocytes [4, 5]. Among such inflammatory cytokines, interleukin (IL) family members, tumor necrosis factor (TNF), have been implicated in the pathological states of OA joints. In addition, Nitric oxide (NO) has been also implicated as a causative factor [6].

2.2 Cartilage Degrading Enzymes

A number of studies have shown that Metalloproteinases (MMPs) [7] and A Disintegrin-like and Metalloproteinases with Thrombospondin Motifs (ADAMTS), especially ADAMTS-4 and 5 play major roles in pathogenesis of OA [8–10].

2.3 Subchondral Bone Changes

A radiographic assessment showed that both subchondral cortical plate and subjacent horizontal trabeculae increased in thickness in early OA phase, prior to joint space narrowing [11]. In a rat anterior cruciate ligament transection (ACLT) model, subchondral bone loss was observed within 2 weeks after surgery followed by significant increased subchondral bone volume compared with control sham knees [12]. Similarly in a canine ALCT-model, thinning of subchondral plate was observed in medial tibial metaphyses where cartilage damage was severe while it was not evident in lateral side where cartilage damage was mild, suggesting strong correlation of cartilage damage and subchondral bone changes [13].

3 Disease Modifying Osteoarthritis Drugs (DMOADS)

While a growing number of studies have revealed pathological conditions and numerous factors contributing to pathogenesis of OA, research in development or discovery of disease modifying osteoarthritis drugs (DMOADs) have been progressed. DMOADS target causative factors for OA, such as increased inflammation, abnormal chondrocyte hypertrophic differentiation, increased cartilage degrading enzymes, increased catalytic activities over anabolic activities in chondrocytes and subchondral bone changes. DMOADs include biochemical compounds, natural products, anti-inflammatory drugs, anti-resorptive drugs and growth factors. Those DMODAs are expected to alleviate patient’s symptoms and slow down the progression of OA or prevent OA. Some pharmacological agents and growth factors are being investigated in clinical trials. In this section, some DMOADS are discussed Fig. 4.1.

Fig. 4.1
figure 00041

A schema showing pathological changes during osteoarthritis (OA) progression and disease modifying osteoarthritis drugs (DMOADs). During OA progression, catabolic factors such as inflammation, cartilage-degrading enzymes increase while anabolic activity such as production of extracelluar matrix (ECM) decreases. OA is also associated with abnormal subchondral bone changes. Drugs targeting these causative factors have been being investigated as DMOADs

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3.1 Inhibitors of Degrading Enzymes and Inflammation

3.1.1 MMP Inhibitors

MMPs are believed to be a major contributor for cartilage degradation, and inhibition of MMPs is rationally attractive treatment for OA. PG-116800, a matrix-metalloproteinase (MMP) inhibitor for MMP-2, -3, -8, -9, -11, -13, and -14 decreased symptoms in patients with mild-to-moderate knee OA [14]. However the MMP inhibitor PG-116800 has also induced side effects in musculoskeletal system [15]. In addition, King et al. reported musculoskeletal side effects in 28 of 35 patients with colorectal hepatic metastases upon treatment with the MMP inhibitor, Marimastat [16]. To avoid musculoskeletal side effects, new drugs that more selectively inhibits MMP-13 were investigated. Oral administration of ALS 1-0635; a selective inhibitor of MMP-13 reduced cartilage degradation in a rat medial menisectomy model without apparent musculoskeletal toxicity [17]. More recently, new MMP-13 inhibitor, that is effective and suitable for intra-articular injection, has been reported [18]. Clinical data will follow.

3.1.2 Aggrecanase Inhibitors

Despite important roles of aggrecanases in the pathogenesis of OA that have been reported, there are only a few reports about aggrecanase inhibitors in OA. The oral administration of aggrecanase inhibitor, AGC-523 reduced aggrecan fragment in a rat meniscal tear model, suggested a potential preventive role in progression of OA [19] and the efficacy of AGC-523 has been now being investigated in a clinical trial.

3.1.3 IL1 Inhibitors

A pro-inflammatory IL1β (beta) is activated by an enzyme, IL-1β (beta) converting enzyme, before being secreted as a mature form. Pralnacasan, a non-peptide inhibitor of IL-1β (beta) converting enzyme, was tested in a collagenase-induced mouse OA model and STR/1N mice, the latter develop OA spontaneously. Pralnacasan reduced joint damage in the two experimental models of OA [20]. However a clinical trial of Pralnacasan was stopped because of its toxicity.

IL-1 receptor antagonist, anakinra has been reported to be moderately effective in patients with active RA when used as monotherapy or in combination with methotrexate [21]. To evaluate the effect of anakinra, a randomized, double-blind, placebo-controlled study was conducted. However a single intra-articular injection of anakinra did not significantly improve symptoms of the patient of OA [22]. Recently effects of a single intra-articular injection of anakinra were tested on patients with acute ACL tear in the randomized control study. Intra-articular injection of anakinra reduced knee pain and improved function over a 2-week interval compared with injection of placebo [23]. Although anakinra might play a beneficial role in reducing inflammation and pain, its effect in OA needs more research.

3.1.4 TNF Antagonists

As in patients with RA, efficacy of TNF antagonists was examined in patients with OA. TNFα (alpha)-antagonists infliximab and etanercept suppressed TNFα (alpha)-induced NO production from human cartilage [24]. In a clinical trial, the efficacy of infliximab was examined in 10 women with bilateral hand erosive OA. Treatment with monthly intra-articular injections of infliximab in each affected proximal and distal interphalangeal joint of the hand significantly reduced pain at the 1-year follow-up. There was a tendency that the treatment with infliximab slows worsening of the radiological score in the hand although it failed to reach statistically significant difference at the 12-month follow-up [25]. In an open-label pilot trial, 12 patients with erosive hand OA received adalimumab 40 mg every other week for 12 weeks. The treatment with adalimumab did not significantly improve the symptoms although modest improvements were observed [26]. Recently results of another randomized double-blind were reported. In the clinical trial, 60 patients with erosive hand OA received 40 mg adalimumab or placebo subcutaneously every 2 weeks during a 12-month. The treatment with adalimumab significantly delayed the progression of joint damage compared to placebo [27].

3.1.5 iNOS Inhibitor

Nitric oxide has been suggested to play important role in pathogenesis of OA In nitric oxide synthase (NOS2)-deficient mice, cartilage proteoglycan depletion induced by the intra-articular injection of Zymosan was markedly reduced [28]. In an experimental dog OA model, administration of N-iminoethyl-l-lysine (l-NIL), a selective inhibitor of inducible nitric oxide synthase (iNOS), orally as a liquid solution decreased the size of the cartilage lesions and reducing the activity of metalloproteases in cartilage and the production of IL-1β (beta) by synovium [29, 30]. The inhibitory effect of the iNOS inhibitor appears to be partially through reduction in production of major catabolic factors such as MMP, IL-1β (beta), peroxynitrite and cyclooxgenase (COX)-2 expression [31]. A clinical trial to examine the disease modifying efficacy of iNOS inhibitor, SD-6010, in overweight and obese subjects with knee OA has been recently completed [32]. The treatment of SD-6010 significantly reduced the rate of joint space narrowing in the obese patients with mild knee OA during the first 48 weeks. However the effect of the treatment with SD-6010 was not significant at 96 weeks and neither in the obese patients with severe OA [33]. Although it may have an effect for short time, its effect appears to be limited in obese patients.

3.2 Growth Factors

3.2.1 Fibroblast Growth Factor (FGF) -18

FGF-18 exerts anabolic effects in human articular chondrocytes, increasing matrix formation [34]. Interestingly, in a rat OA model in which OA was surgically induced by medial meniscus injury, bi-weekly intra-articular injections of FGF18 for 3 weeks increased cartilage thickness of articular surface and the joint periphery, resulted in significant reductions in cartilage degeneration scores [35]. Clinical trials of treatment of OA by intra-articular injection of FGF18 have been recently completed [36, 37]. Results of the studies are not yet available and needs to be awaited.

3.2.2 Bone Morphogenetic Protein (BMP)-7

BMP-7 has been reported to have potent anabolic effects on chondrocytes. Recombinant human (rh)BMP -7 stimulated proteoglycan synthesis and collagen synthesis in human chondrocytes and counteracted against the down-regulation of proteoglycan synthesis induced by low doses of IL-1β (beta) [38, 39]. In addition, stimulatory effects of BMP-7 on cartilage repair have been reported [40]. RhBMP-7 promoted repair of full-thickness osteochondral defects in a dog [41] and in a goat [42] model. Furthermore the efficacy of intra-articular injection of BMP-7 was examined in a sheep impact cartilage injury model. Sheep knee joints that received rhBMP-7 immediately after and 3 weeks after injury exhibited less cartilage damage compared with the non-injected group [43]. Similarly weekly intra-articular injection BMP-7 prevented OA progression in a rabbit ACLT model without obvious adverse effects on the joint [44] and inhibited OA progression induced by excessive treadmill running in rats [45]. In a phase I clinical trial, double-blind, randomized, placebo-controlled, was conducted to examine the safety and efficacy of BMP-7 for treatment of patients with knee OA. In the phase I clinical trial, no major adverse events was observed and injection of 0.1 and 0.3 mg BMP-7 more improved the symptoms of the patients than injection of placebo [46]. A phase II clinical trial to further examine the efficacy of BMP-7 in OA has been also completed [47].although the results have not yet been reported. Currently intra-articular injection of BMP-7 appears to be promising for treatment of OA, but it needs more research to determine whether the injection of BMP-7 can delay progression of OA and long term effect of the injection.

3.2.3 Platelet-Rich Plasma (PRP)

Platelets are known to contain a variety of growth factors, such as FGF-2, insulin-like growth factor 1 (IGF-1), platelet-derived growth factor (PDGF), Tansforming Growth Factor (TGF) β (beta), vascular endothelial growth factor (VEGF), epidermal growth factor (EGF). PRP is made from patient’s peripheral blood followed by centrifuge, producing platelet concentrates. Because PRP is relatively safe and easy to prepare, PRP has gained popularity in orthopaedic field for enhancing healing of bone, ligament injury, muscle injury and tendinopathy [48, 49].

The efficacy of PRP injection in treatment for patients with cartilage degeneration and OA was also examined. Intra-articular injection of PRP reduced pain and improved clinical scores over the 6 month-period although its effect decreased at the longer follow-up [50, 51]. In addition, PRP injections more improved clinical symptoms than hyaluronic acid injections [52, 53]. Although PRP can be effective treatment for OA, its disease modifying effect of OA has not been clarified. The effect of PRP might be through anti-inflammatory effects [54, 55] rather than anabolic effect on cartilage. In a pilot study, PRP was added to the autologous matrix-induced chondrogenesis (AMIC) technique to treat cartilage defect in the patella. However the addition of PRP to AMIC did not produce obvious beneficial effects [56]. One of the important issues in research of PRP is methodological variations in preparation of PRP. Currently no standardized technique exists and the differences in preparation techniques, making it difficult to obtain generalized valid data. Further detailed basic studies about efficacy of PRP in cartilage regeneration and OA are required.

3.3 Drugs Targeting Subchondral Bone Changes

3.3.1 Calcitonin

Calcitonin has been widely used for treatment for osteoporosis it has also been introduced for OA treatment based on the hypothesis that normalization of subchondral bone could prevent OA progression. In a dog ACLT model, reduced bone mineral density (BMD) was observed and the treatment of calcitonin by nasal spray prevented the reduction of BMD and reduced cartilage break down caused by the ACLT [57, 58]. A randomized, double blind, placebo-controlled clinical trial was conducted in 152 postmenopausal women. Oral intake of the 1.0 mg salmon calcitonin reduced urinary excretion of C-terminal telopeptide of collagen type II (CTX-II), suggested an effect of calcitonin in prevention of OA progression [59]. Similarly, in clinical trials including 41 patients, oral intake of salmon calcitonin for 84 days significantly decreased in the levels of CTX-II, C2C, and MMP-13 [60]. The effect of the calcitonin could exert through not only on changes in BMD but also direct effect on cartilage [61, 62]. Calcitonin receptor was expressed in chondrocytes and the treatment of calcitonin stimulated the production of proteoglycan and pro-peptides of collagen type II in human OA cartilage explants [63]. Very recently, Sondergaard et al. reported that OA progression induced by destabilization of medial meniscus was significantly reduced in transgenic mice over-expressing salmon calcitonin compared with in wild type mice [64]. A clinical trial examining efficacy and safety of oral Salmon calcitonin in patients with knee has been recently completed [65].

3.3.2 Bisphosophonates

Bisphosphonates have been also used for osteoporosis and they were expected to improve the quality of subchondral bone in OA. In a rat ACLT model, treatment of alendronate subcutaneouslly suppressed subchondral bone resorption and reduced the incidence and area of osteophyte formation [66]. Similarly in a rabbit ACLT model, alendronate reduced subchondral bone resorption and delayed the cartilage degeneration [67, 68]. One study shows that among 818 postmenopausal women who received alendronate and estrogen had less subchondral bone attrition and bone marrow edema-like abnormalities in the knee [69]. In addition, the treatment with Alendronate significantly reduced knee pain assessed by WOMAC scores in the elderly women [69]. In a double-blind placebo-controlled clinical study including 231 patients with mild to moderate knee OA, treatment with 15 mg risedronate improved the WOMAC index. In addition, there was a trend that risedronate delays joint space narrowing [70]. In a relatively large study in which 2,483 patients with medial compartment knee were enrolled, risedronate reduced symptoms of OA and reduced C-terminal crosslinking telopeptide of type II collagen, a cartilage degradation marker. However the treatments with risedronate did not significantly reduce joint space narrowing assessed by radiography [71]. Very recently it has been reported that the intravenous infusion of zoledronic acid reduced knee pain and the size of the bone marrow lesion are in patients with knee OA [72].

4 Conclusions

Recent growing number of basic OA research has provided new insights into pathogenesis of OA and also has led to clinical trials for treatment of OA. Despite numerous pharmacological interventions for treatment of OA have been tried, to date none of pharmacological drugs has shown definite disease modifying effect. Therefore currently early diagnosis and intervention for preventing progression of OA before causing global alterations in joint homeostasis, seems to be an important approach for producing successful results. More research is required to discover new therapeutic approach and effective treatments for OA.