Calcium Pyrophosphate Dihydrate Deposition Disease

Chapter 14

Calcium Pyrophosphate Dihydrate Deposition Disease Orestis L. Katsamenis1, 2 and Nikolaos Bouropoulos2, 3 mVIS X-ray Imaging Centre, Faculty of Engineering and the Environment, University of Southampton, Highfield, Southampton, UK; 2Department of

1

Materials Science, University of Patras, Patras, Greece; 3Foundation for Research and Technology, Hellas-Institute of Chemical Engineering and High Temperature Chemical ProcessesdFORTH/ ICE-HT, Patras, Greece

14.1 PHYSIOLOGICAL AND PATHOLOGICAL MINERALIZATION IN THE HUMAN BODY Development and deposition of amorphous or crystalline inorganic phases occur in a large number of biological systems and it is a vital process of their physiological function. From single cells, bacteria, and bacterial colonies up to more complex organisms like birds, plants, and mammals, formation and deposition of crystal is a fundamental part of their life circle. This process is usually referred to as “mineralization” or “calcification” although to date the notion that distinction should be made between these two terms is gaining ground. This idea is established on the basis that many of the minerals formed in biological systems contain no calcium, and thus the use of the term “calcification” to describe deposits of such nature is inappropriate [1]. In this chapter, the term “calcification” will only be used when we refer to calcium-based depositions. In humans, physiological calcification starts occurring in the early stages of embryonic development with the formation of the skeleton and continuesdwith much lower ratedup until the end of the life cycle of the individual with the development of the teeth, bone growth, and bone remodeling. Bone formation is steered by specialized cells (the osteoblasts) and according to the most well-accepted model is the result of a “classical” crystal growth process, which involves the nucleation, growth, and proliferation of biological apatite [2] within the hierarchically arranged collagen fibrils [3] and the intrafibrillar space [4]. The resulting tissue is a hard and tough structure, which facilitates movement, provides protection and serves as the main repository of calcium and phosphates of the body [5]. During the life span of the individual, bone is continuously adapting to its environment and self-repairs; a process called remodeling [6]. Teeth are the outcome of a more complex calcification process, which results in the development of a hard and stiff structure, which has a vital role in mastication. As in the case of bone, teeth formation is also steered by cells (odontoblasts), which control apatite formation and growth [7]. Calcification of bones and teeth is the only physiological mineralization process that occurs in the human body. Crystals, however, are often formed and accumulated in various other sites of the body. The term “pathological mineralization” or “pathological calcification” has been used to describe the presence of such crystals. Common sites of pathological mineralization involve the surface of the teeth [8,9], arterial walls [10], articular cartilage [11], gallbladder, [12] and kidneys [13] but effectively almost all tissues can be “attacked” by crystal deposits. Occurrence of pathological mineralization is not limited to biological tissues. Synthetic grafts such as heart valves [14], intraocular lenses [15,16], stents, and catheters [17,18] are also common sites of pathological mineralization. The mechanism behind the initiation and the growth of pathological crystal deposits has been in the epicenter of the mineralization-related research community for almost a century; since Leriche and Policard showed that bone-like tissue can be formed by fibroblasts at almost every site of the body under certain circumstances [19]. Yet, to a large extend the exact mechanism still remains unknown. An interesting aspect of the ongoing debate has to do with the factors that induce or inhibit crystal formation with some researchers supporting that pathological mineralization is an “active,” cell-mediated process [20], while others support the hypothesis that mineralization will occur “passively” at any site if cell-produced inhibition factors are not present [21,22].

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374 Mineral Scales and Deposits

Pathological mineralization can be symptomatic or asymptomatic [23], idiopathic [24] or the result of another primary pathology such as trauma, inflammation, [25] or tumor [26]. In terms of composition, pathological depositions found in human body are mainly calcium-based compounds, such as carbonate apatite (Ca10(PO4)6(CO3)$H2O), calcium pyrophosphate dihydrate (CPPD, Ca2P2O7$2H2O), and calcium oxalate dihydrate (CaC2O4$2H2O), as well as organic crystals and magnesium-based deposits. Table 14.1 summarizes the composition of various pathologically mineralized compounds and the sites in the human body and the anatomical locations in which they can be found.

TABLE 14.1 Composition and the Occurrence Sites in the Human Body for Various Pathologically Mineralized Compounds Calcium hydrogen urate

Ca(C5H3N4O3)2

Kidneys

Carbonated apatite (dahlite)

Ca10(PO4)6(CO3)$H2O

Joints, liver, gallbladder, prostate, salivary glands, aorta, skin, and muscle

Calcium pyrophosphate dihydrate (CPPD)

Ca2P2O7$2H2O

Joints, kidneys

Calcium citrate tetrahydrate

Ca3(C6H5O7)2$4H2O

Prostate

Tricalcium phosphate

Ca3(PO4)2

Joints

Calcium phosphates hydroxyapatite

Ca5(PO4)3OH

Breast, salivary glands

Octacalcium phosphate (OCP)

Ca8(HPO4)2(PO4)4$5H2O

Joints, kidneys, salivary glands

Whitlockite

Ca9Mg(HPO4)(PO4)6

Joints, kidneys, prostate, salivary glands, aorta

Calcium oxalate dihydrate (weddellite, COD)

CaC2O4$2H2O

Breast, kidneys, prostate

Calcium oxalate trihydrate (caoxite, COT)

CaC2O4$3H2O

Kidneys

Calcium oxalate monohydrate (whewellite, COM)

CaC2O4$H2O

Kidneys, prostate

Amorphous carbonated calcium apatite (CaP)

Ca10(PO4)6(CO3)x(OH)2
2x, with 0  x  1

Kidneys, liver, gallbladder, salivary glands

Calcium carbonate polymorphs (calcite, aragonite, vaterite)

CaCO3

Liver, gallbladder, pancreas

Brushite

CaHPO4$2H2O

Kidneys, prostate

Magnesium hydrogen urate

Mg(C5H3N4O3)2$8H2O

Kidneys

Magnesium phosphates (newberyite)

MgHPO4$3H2O

Kidneys

Magnesium ammonium phosphates hexahydrate (struvite)

MgNH4PO4$6H2O

Kidneys

Dittmarite

MgNH4PO4$H2O

Kidneys

2þ

Calcium palmitate

[C16H31O2]2$Ca

Liver, gallbladder

Cholesterol

C27H46O

Liver, gallbladder

Calcium bilirubinates

C33H36N4O6$x-Ca

Liver, gallbladder

Sodium hydrogen urate

C5H3N4O3$Na

Kidneys

Ammonium hydrogen urate (urate)

C5H3N4O3NH4

Kidneys

Xanthine

C5H4N4O2

Kidneys

Uric acid anhydrous

C5H4N4O3

Kidneys

Uric acid monohydrate

C5H4N4O3$1H2O

Kidneys

Uric acid dihydrate

C5H4N4O3$2H2O

Kidneys

Cystine

C6H12N2O4S2

Kidneys

Leucine

C6H13NO2

Kidneys

Tyrosine

C9H11NO3

Kidneys

Adapted from [107] with permission and modified.

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CPPD (Ca2P2O7$2H2O) crystal depositions are among the most commonly occurring types of pathological calcifications. The first report of CPPD in the human body was published in early 1960s by McCarty et al., which were the first to identify CPPD crystals in the synovial fluid of arthritic patients [27e29]. Since then a vast amount of work has been done to better understand the factors responsible for the formation and deposition of CPPD crystals in vivo and to find effective methods for stopping the progress and removing CPPD depositions. However, despite our current deeper understanding of the disease, no such treatment has been discovered yet [30].

14.2 THE NATURE AND COMPOSITION OF CPPD 14.2.1 Calcium Phosphates and Pyrophosphates All calcium phosphates are members of a “superfamily” of inorganic compounds, which consist of three basic elements: calcium, phosphorus, and oxygen. Phosphorus and oxygen are then combined together to form anions, which subdivide the calcium phosphate family into smaller groups (families) named after these phosphate anions. As a result, all calcium phosphates, which contain the orthophosphate ion (PO3
4 ) are part of the calcium orthophosphate family, the ones containing the pyrophosphate group (P2O4
7 ) are part of the calcium pyrophosphate (CPP) family and the same holds true n
for those containing the meta-(PO
3 ) and poly-[(PO3)n ] phosphate groups. Among these compounds, are some that contain hydrogen, which can be incorporated in the structure in form of acidic orthophosphate anion (e.g., HPO2
4 ), hydroxide (Ca10(PO4)6(OH)2) and/or incorporated water, like in the case of CPPD (Ca2P2O7$2H2O) [31,32]. The CPP family was extensively studied by Brown and colleagues who prepared and characterized 25 CPP compounds [33]. Among them eight CPPs where containing ammonium (e.g., Ca(NH4)2P2O7$H2O; Ca3(NH4)2(P2O7)2$H2O; etc.) and 10 containing potassium (e.g., CaK2P2O7; CaK2P2O7$4H2O; etc.). These compounds were grouped under the subfamily of “calcium ammonium pyrophosphates” and “calcium potassium pyrophosphates” respectively. The rest were hydrated or dehydrated CPPs containing only calcium, phosphorus, and oxygen and were grouped under the “CPPs” subfamily named after the general family name. The CPP subfamily contains five compounds, four hydrated and one anhydrous, among which there are also two pairs of allomorphs of hydrated CPPs. The basic CPPs are as follows: (1) CPPD (Ca2P2O7$2H2O); (2) calcium pyrophosphate tetrahydrate (CPPT, Ca2P2O7$4H2O); (3) tricalcium dihydrogen pyrophosphate tetrahydrate (Ca3H2(P2O7)$4H2O); tricalcium dihydrogen pyrophosphate monohydrate (Ca3H2(P2O7)$H2O); and the anhydrous calcium acid pyrophosphate (CaH2P2O7).

14.2.2 Crystal Structure of CPPD CPPD (Ca2P2O7.2H2O) exists in three crystalline forms: triclinic calcium pyrophosphate dihydrate (t-CPPD), monoclinic calcium pyrophosphate dihydrate (m-CPPD), and hexagonal calcium pyrophosphate dihydrate (h-CPPD). The crystal parameters of these allomorphs are given in Table 14.2. The triclinic and monoclinic forms are of particular interest because of their involvement in CPP crystal deposition disease. h-CPPD, or any of the other CPPs mentioned in Section 14.2.1, has never been identified in vivo [34]. The triclinic allomorph of CPPD (Figure 14.1(a)) forms elongated plank-like crystals and is the most stable of all three forms of CPPD. m-CPPD (Figure 14.1(b)) forms needlelike, “squat” rhomboid or cuboid shaped crystals and its unit cell is twice the size of the unit cell of t-CPPD (Table 14.2). h-CPPD forms needlelike crystals as well and occurs as a result of unit cell rearrangement of a precursor CPPT phase following the loss of two structural water molecules.

14.3 MECHANISM OF CPPD CALCIFICATION 14.3.1 Generation and Supersaturation of Inorganic Pyrophosphate in the Human Body As in every crystallization process, precipitation of CPPD requires the development of supersaturation with respect to the precipitating salt’s constituent ions, that is calcium (Ca2þ) and inorganic pyrophosphate (PPi). PPi is an ion comprised of two inorganic phosphate (Pi) molecules bound together via a high-energy ester bound (Figure 14.2). In the human body, normal calcium concentration in plasma is approximately 2.5 mmol/L of which 1.2 mmol/L is free ions and the rest protein-bounded and complexed [35]. Normal PPi concentration is three orders of magnitude smaller, approximately 3.5 mmol/L [36]. In the presence of such free calcium ion concentration, a minimum PPi concentration of 40e45 mmol/L is required for initiation of CPPD crystal growth and this figure increases to 175 mmol/L in the presence of 0.5 mmol/L of

376 Mineral Scales and Deposits

TABLE 14.2 Unit Cell Data (a, b, c); Lattice Constants (a, b, g), Density (r), Number of Molecules in the Unit Cell (Z), and Space Groups for the Three Allomorphs of Calcium Pyrophosphate Dihydrate and Orthorhombic CPPT, the Precursor Phase of h-CPPD. Standard Deviations of Experimentally Defined Data Are Presented in Parentheses t-CPPD

m-CPPD

h-CPPD

˚) a(A

7.365(4)

8.07

11.782(4)

˚) b(A

8.287(4)

14.76

11.782(4)

˚) c(A

6.691(4)

6.25

9.777(2)

a(deg)

102.96

90

90

b(deg)

72.73(1)

103

90

95.01(1)

90

120

r(g/cm )

2.56

2.66

2.46

Z

2

4

6

Space group

P1

e

P63cm

g(deg) 3

CPPT, calcium pyrophosphate tetrahydrate; CPPD, calcium pyrophosphate dihydrate. Adapted from [83] with permission.

(a)

(b)

FIGURE 14.1 Scanning electron microscopy images of (a) triclinic calcium pyrophosphate dihydrate and (b) monoclinic calcium pyrophosphate dihydrate crystals. (a) was produced by the authors and (b) is adapted from [138] and reprinted with permission.

FIGURE 14.2 Structural formula of inorganic pyrophosphate ion, [P2O7]4
. Public domain via Wikimedia commons.

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Mg2þ [37]. This PPi concentration is well above the physiological levels meaning that for CPPD to start precipitating, the levels of PPi have to undergo a tenfold increase. However, plasma calcium and PPi levels are under homeostatic control and their concentration remains nearly constant even in patients with CPPD crystal deposits [38]. This has led to the notion that precipitation of CPPD crystals is steered by local rather than systemic factors [39]. In the hyaline articular cartilage and fibrocartilage, where CPPD crystals mostly develop, concentration of PPi is higher than the one measured in plasma. Accepting the simplified assumption that the PPi concentration of the articular cartilage is similar to that of its synovial fluid, normal concentration in these sites ranges between 9 and 10 mmol/L [40], which in case of pyrophosphate arthropathy can be increased up to 16 e25 [41]. However, it is important to note that the aforementioned assumption is not always accurate as PPi levels in the synovial fluid can be affected by various factors like, for example, the synovial flow rate or inflammation [40]. One of the reasons PPi levels are elevated in articular cartilage is its ability to suppress hydroxyapatite nucleation and growth [42,43]. It is believed that this property of PPi “protects” the collagenous tissues that are not to be mineralized [39,44,45]. However, abnormalities on the molecular mechanism responsible for keeping PPi levels balanced can cause deviation of PPi concentration from the physiological levels and consequently lead to pathological calcification. In the human body, generation of PPi occurs intracellularly mainly by two pathways; as a metabolic product of numerous cell-mediated bioreactions or by the hydrolysis of adenosine triphosphate (ATP) and the phosphodiester I bond in purine and pyrimidine by the enzyme nucleoside triphosphate pyrophosphohydrolase [43,45]. The generated PPi ions are then being pumped to the extracellular space by the multipass transmembrane progressive ankylosis protein (ANK). This molecular pump appears to have a critical role on the concentration levels of PPi, in both the intra- and intercellular spaces. Malfunction or loss of this ANK-mediated mechanism can result in decreased extracellular- and increased intracellular PPi levels (Figure 14.3) [46]. In turn, this can lead to local PPi supersaturation and nucleation of CPPD or inefficient inhibition of basic calcium phosphate crystallization and precipitation of Hyrdroxyapatite (HAP).

FIGURE 14.3 Schematic diagram of the potential mechanism of extracellular inorganic pyrophosphate (PPi) generation based on Ho et al.’s model [46]. PPi is generated intracellularly by either of the two pathways and their intracellular and extracellular levels are kept in control via the ANK-mediated pump, which channels PPi from the intracellular to the extracellular space. Malfunctioning pump could result in inefficient or complete blockage of PPi transfer to the extracellular space, reducing the extracellular PPi levels and increasing the intracellular ones. In this case, the local high concentration of intracellular PPi could result in calcium pyrophosphate dihydrate (CPPD) precipitation, while at the same time the low extracellular PPi level results in insufficient inhibition of hydroxyapatite precipitation. High levels of extracellular PPi can in turn occur as the result of cell-mediated excess generation of PPi as shown in the bottom diagram. The exact mechanism by which this excess generation occurs is not entirely clear, but there is strong evidence to support that this is, at least partially, associated with increased nucleoside triphosphate pyrophosphohydrolase activity [39,45].

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FIGURE 14.4 Matrix vesicle-mediated nucleation and growth of mineral (biological apatite) crystals in rat growth plate cartilage. During phase 1, (a) a metastable solution of calcium and phosphate is developed in the intravesicular space as a result of their affinity for lipids and Ca-binding proteins, which are located in the interior of the vesicle’s membrane. Phase 2 (b) is defined by crystal proliferation and exposure of the preformed crystals to the extravesicular space. Adapted from [139] and reprinted with permission.

14.3.2 Nucleation and Growth of CPPD Crystals The most common sites of pathologically occurring CPPD depositions are undoubtedly the articular cartilage and fibrocartilaginous tissues like the knee- and shoulder menisci. Deposition of such minerals in these tissues has been associated with the presence of hypertrophic chondrocytes and release of extracellular matrix vesicles (MVs), which promote mineralization [47]. Chondrocytes are the cells responsible for producing the tissue matrix by laying down collagen, proteoglycans, and other, noncollagenous proteins [48]. On sites where physiological mineralization takes place, like for example in the vertebral bodies, growth plates, and teeth, chondrocytes also play a very important role in the mineralization process. Release of extracellular MVs by chondrocytes, promote the formation of inorganic salts by tuning the local ion concentration in their lumen and initiating nucleation. MVs are small, 50e200 nm, vesicles made of a lipid bilayer membrane, similar to that found in cells, populated with a number of proteins and enzymes. Upon secretion, the MVs are being encapsulated into the tissue matrix where they act as nanoreactors for the initiation of matrix mineralization. To be able to do this, MVs utilize the aforementioned proteins and enzymes of their membrane for controlling the Ca2þ uptake and the homeostasis of Pi ions [49,50]. Under the appropriate conditions, i.e., ion concentration, pH, and lack of inhibition factors, the mineralization process begins. During its first phase, crystal nucleation occurs within the MVs as a result of a metastable solution development. Crystal proliferation is then taking place and eventually the newly formed crystals grow large enough to penetrate the membrane and escape into the extravesicular space (Figure 14.4). The latter step, is defined as “phase two” and is the critical point at which the control of the mineralization process is “transferred” from the MVs to the collagenous matrix [50].

14.4 PATHOLOGICAL DEPOSITION OF CPPD IN THE HUMAN BODY 14.4.1 Historical Note Occurrence of CPPD crystals in the human body was first reported in early 1960s, by McCarty and coworkers. The team had extracted from osteoarthritic joint fluids, samples of “unknown” crystals, which could not be digested by uricase; a specific enzyme capable of digesting the uric acid crystals. They examined these crystals by means of polarized light microscopy (PLM), infrared (IR) spectrometry, and X-ray diffractometry (XRD) and, to their surprise, they find that the IR and XRD “signatures” of the “unknown” crystals corresponded to the triclinic (t-) and monoclinic (m-) form of CPPD [27e29]. A kind of crystals that had never before been reported occurring in the human body. They named this constitution “pseudogout” to stress the fact patients with CPPD crystal deposits developed in their joints displayed a clinical picture similar to the one seen in patients with uric acid deposits; a condition known as “gout” [11]. The symptoms included acute attack of synovitis and were accompanied with radiologic findings such as linear radiodensities in the articular cartilage and deposits in fibrocartilaginous structures [51]. Since then, a great effort has been made to develop a greater understanding of the pathology. Occurrence of CPPD deposits has been reported in numerous locations including other joints such as the shoulder, elbow, spine, and organs and soft tissues (Section 14.4.3).

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14.4.2 Nomenclature Since the first description of the condition under the term “pseudogout” by McCarty and the coworkers, a large number of terms have been used to describe the CPPD crystal deposition disease phenotype. The nomenclature uses terms as “chondrocalcinosis,” which is used as a more general term when referring to pathological calcification of cartilage, “CPP crystal deposition disease,” “Pyrophosphate arthropathy,” and of course “pseudogout.” However, based on the logic behind the use of term “pseudogout” for a syndrome mimicking the symptoms and phenotype of Gout in absence of uric acid crystals, a plethora of “pseudo-” syndromes soon emerged for describing the various proliferations of the disease. Under this framework, terms such as “pseudorheumatoid arthritis,” “pseudoosteoarthritis” and “pseudoneuropathic arthritis” were also added causing even more confusion [25,52]. In an effort to achieve consensus regarding, among others, the nomenclature of CPPD deposition disease, a task force of 15 experts from 10 countries, members of the European League Against Rheumatism (EULAR), was established under the name “EULAR CPPD Task Force.” The results of this action published in 2011, recommended that “‘CPPD’ should be the umbrella term that includes acute calcium pyrophosphate (CPP) crystal arthritis, osteoarthritis (OA) with CPPD and chronic CPP crystal inflammatory arthritis.” It is important to note, however, that in the aforementioned term CPPD stands for “calcium pyrophosphate deposition,” i.e., the clinical condition of CPP crystal deposition, and not for “calcium pyrophosphate dihydrate.” The committee decided to refer to the CPPD crystals using the general term “CPP” in accordance to the well-accepted use of the term “sodium urate” for referring to “monosodium urate monohydrate” in the case of gout [25]. However, as this is a more general and not a solely clinical chapter, the term CPPD is used for referring to calcium pyrophosphate dihydrate and not to the clinical condition. To avoid confusion the disease will always be referred to as “CPP crystal deposition disease.”

14.4.3 Clinical Manifestation, Morphology, and Anatomical Locations of CPPD Crystal Deposits The clinical manifestation of CPP crystal deposition disease varies widely among individuals. Some patients suffer acute attacks or chronic pain while in others the presence of CPP crystals is asymptomatic [53]. Acute attacks of CPP crystal deposition disease show symptoms typical to other crystal-induced attacks. These are severe pain, swelling, and stiffness of the involved site and development of erythema. In most of these cases, the symptoms start gradually and reach a peak intensity within 24 h [54]. The size, the type, and the morphology of CPPD crystals can also affect the clinical manifestation of CPP crystal deposition disease as shown by Swan et al. In their clinical study, CPPD crystals were extracted from the synovial fluid of patients during an acute attack of the disease (acute sample) and again later when the attack had subsided (interval sample). Morphological and crystallographic analysis showed that there was a greater crystal load, larger crystals, and a greater ratio of m- to t-CPPD crystals during the episode of the attack in comparison to the period in which the inflammation had subsided [55]. The most common sites to be involved in CPP crystal deposition disease are the knee joint, the wrist, the shoulder, and the elbow. Figure 14.5 and Table 14.3 summarize the anatomical locations in which CPPD crystals have been found. Effectively, all soft tissues can become the substrate for crystallization and growth of CPPD crystals. However, CPPD crystal development is mostly observed in fibrocartilaginous tissues and in the hyaline cartilage in joints. In most of the cases, CPPD crystal deposition sites resemble colonies of highly crystallized CPPD developed within the extracellular matrix of the tissue. Figure 14.6 presents an example of such CPPD colonies developed in human knee menisci. As can be seen, the crystal colony has been developed in the intrafibrillar space and has completely disrupted the cohesion of the tissue. In some regions, monocrystals as big as 50e60 mm can be observed even under the light microscope (arrows and insets in Figure 14.6(a) and (b)). A closer look on these colonies reveals the high degree of crystallinity of these areas (Figure 14.7). SEM and AFM microscopy revealed the characteristic crystal morphology of the monoclinic and triclinic allomorphs of CPPD; that is the “squat” rhomboid and cuboid-shaped crystals of m-CPPD, and the elongated rodlike shaped ones, which correspond to the t-CPPD [55e57]. It is worth noting, that in these areas no collagen fibers can be observed. Some organic nonfibrillar material, however, possibly a mixture of noncollagenous proteins and polysaccharides like glycosaminoglycans, are present and allocated in the intercrystalline space. There is no way of knowing from these images whether this organic material was present at the site prior to the formation of the crystals, as a result of tissue degeneration, for example, or if it accumulated there after or during the crystallization process. However, it seems that this material acts as “glue” facilitating attachment between the individual crystals and supporting the integrity of the colony.

380 Mineral Scales and Deposits

FIGURE 14.5 Diagram representing the various locations reported in the literature on which calcium pyrophosphate dihydrate crystals deposition have been identified.

Unstructured proteins are known to act as cohesion media and the effectiveness of their cohesion ability increases with the presence of ions such as Ca2þ and La3þ [58e60].

14.4.4 Coexistence with Other Pathologies Occurrence of CPPD crystal deposits is often observed in coexistence with degenerative conditions such as OA [61] or mucoid degeneration [62] but the exact relation between the development of the CPPD crystals and the pathology has not yet been clarified. In the literature, most of the studies support that there is a clear correlation between CPPD crystal deposition and OA [63,64]. However, some of them support that chondrocalcinosis, i.e., the clinical term for crystal deposition in the articular cartilage, leads to OA [65], while others the exact opposite. Namely, that chondrocalcinosis occurs as the result of degenerative conditions, like OA [66]. This controversy originated from the different perceptions of how the conditions favoring crystal precipitation or the ones leading to tissue degeneration are established. In this context, supporters of the first pathway argue that degeneration occurs either as a result of changes in the biomechanical properties of the calcified tissue [67] or as a result of abnormal cell behavior at the presence of the crystals [65]. On the other hand, supporters of the second pathway claim that degenerated matrix containing proteoglycans, debris of cellular components, and degenerated collagen fibers, create the appropriate conditions under which crystal precipitation can occur [66]. It is noteworthy, however, that there have also been studies that support that CPPD deposition is independent of the development of OA [68,69]. Despite the ongoing debate with regards to the relationship of the CPP crystal deposition disease to other pathologies, it is commonly accepted that aging, OA, previous trauma or injury, some metabolic disorders, as well as heredity are critical risk factors for the development of CPPD crystal deposition [25]. Crystal-induced arthritis sometimes coexists also with septic or bacterial arthritis [54,70,71]; a condition in which a joint is infected with germs or bacteria causing intense pain and swelling of the joint. Septic arthritis is considered a rheumatological emergency, which if untreated can lead to rapid destruction of the joint [72]. However, distinguishing among crystal-induced arthritis, septic arthritis or coexistence of crystal with septic arthritis is not an easy task as all of them exhibit similar clinical picture (Section 14.4.3), yet require different treatment. In rare cases, CPPD crystal depositions manifest as tophaceous lesions. The lesions consist of massive colonies of CPPD crystals embedded in a chondromucoid matrix (Figure 14.8) and can be symptomatic or asymptomatic [73,74]. Tumoral CPPD depositions have been reported in a variety of anatomical locations, with the temporomandibular joint, the

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TABLE 14.3 Summary of the Various Anatomical Locations of the Human Body in Which CPPD Crystals Have Been Found Location

References

Knee Articular cartilage

[108]

Synovial membrane

[109]

Meniscus

[62,110]

Vertebral structures Intervertebral disk

[111,112]

Apophyseal and sacroiliac joints

[111]

Posterior longitudinal ligament

[111]

Interspinous and supraspinous ligaments

[111]

Ligamentum flavum

[111]

Interosseous sacroiliac ligament

[111]

Transverse atlas ligament

[111]

Posterior median atlantoaxial joint

[111]

Ligamenta flava

[113]

Cervical ligamentum flavum

[114]

Craniocervical junction

[115]

Filum terminale

[116]

Transverse ligament of atlas

[111,117]

Shoulder/acromioclavicular joint

[118,119]

Wrist

[120e123]

Elbow

[124,125]

Temporomandibular joint (atypical location)

[73,126e129]

Metatarsophalangeal joint of the great toe (atypical location)

[73,130]

The hip joint (atypical location)

[73,131]

Cervical spine (atypical location)

[73]

Pubic

[132]

Tendons

[133,134]

Sclera (atypical location)

[91]

Spleen

[135]

In tumors

[136,137]

cervical spine and the hand being the most common ones [74]. Table 14.4 presents the anatomic locations of tumoral CPPD crystal depositions (until 2001) as reported by Yamakawa and colleagues in [74].

14.4.5 Implications on the Mechanical Properties of the Tissue As described in Section 14.4.3, CPPD forms large, dense, and highly crystalline colonies, which develop in the intrafibrillar space disrupting the cohesion of the tissue. The presence of such structures in the body of soft tissues alters their

382 Mineral Scales and Deposits

FIGURE 14.6 The presented sections are 4 mm thick histopathological sections of formalin-fixed and paraffin-embedded human knee meniscal samples with calcium pyrophosphate dihydrate (CPPD) crystal deposits. Big monocrystals, approximately 50e60 mm long, can be clearly seen in both (a) and (b). (b) and (c) show the development of CPPD crystal “colony” within the meniscal tissue. The main growth direction of the “colony” is following the orientation of the collagen fibers expanding parallel to their longitudinal axis. The presence of such structures in the meniscal, or other tissues could act as a defect center and significantly alter the biomechanical properties of the host tissue. Adapted from [62] and reprinted with permission.

FIGURE 14.7 Scanning electron microscopy (a, b) and atomic force microscopy (c, d) images of a representative area of a calcium pyrophosphate dihydrate (CPPD) “colony” formed on a human knee meniscus. Development of both triclinic (t) and monoclinic (m) allomorphs of CPPD is commonly seen in these areas. The cohesion of the “colony” is mediated by the presence of a nonfibrillar organic substance, which acts as “glue” facilitating attachment between the individual crystals (insets and arrows). Adapted from [62] and reprinted with permission.

(a)

(b)

(c)

(a)

(b)

(c)

(d)

Calcium Pyrophosphate Dihydrate Deposition Disease Chapter | 14

(a)

(b)

(c)

(d)

FIGURE 14.8 (a) X-ray image showing a calcium pyrophosphate dihydrate (CPPD) mass in the ulnar aspect of the left thumb; (b) Axial view of T2-weighted MRI demonstrating a tumorous CPPD mass (arrows) of the infratemporal fossa adjacent to the right temporomandibular joint; (c) Cut surface of excised calcified mass from the metatarsophalangeal joint of a patient with painful great toe showing solid, chalky white appearance; (d) Decalcified section stained with hematoxylin-eosin stain, showing the development of chondromyxoid matrix and loss of basophilia at the site of removed CPPD deposits (arrows). Adapted from [74] and [73] with permission.

TABLE 14.4 Anatomic Locations of Reported Cases of Tumoral CPPD Crystal Depositions (Since 2001) Anatomical Location

Number of Cases (%)

Central (head and neck) type

33 (61)

Temporomandibular joint

20 (37)

Cervical spine

12 (22)

Parotid gland

1 (2)

Distal (extremity) type

21 (39)

Upper extremities

15 (28)

Hand

10 (18)

Wrist

2 (4)

Elbow

1 (2)

Shoulder

2 (4)

Lower extremities

6 (11)

Toe

3 (5.5)

Hip

3 (5.5)

Total

54 (100)

CPPD, calcium pyrophosphate dihydrate. Adapted from [74] and reprinted with permission.

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384 Mineral Scales and Deposits

mechanical properties by inhomogeneously increasing the modulus of elasticity and could also act as defect centers playing a significant role on the mechanism of tissue’s lesion. In fact, CPPD deposits have been associated with tissue failure, like, for example, in the case of pathologically calcified tendons [75e77]. The exact mechanism of tissue failure in these cases is not entirely clear. However, it is believed to be associated with the crystal-induced inflammation and some tribological phenomena (e.g., attrition). Future experimental- and computational modeling studies are needed in this field.

14.4.6 Treatment and Management of CPP Crystal Deposition Disease Finding an effective way of dissolving, retarding, and ultimately preventing the precipitation of CPPD crystals in vivo has puzzled the arthritis-related research community for many years. For this purpose, a number of pharmacological agents have been used and some clinical trials have been conducted, resulting in promising, yet not conclusive, results. Magnesium, alkaline phosphatase, and various polyphosphates are some of these agents. In vitro studies have shown that magnesium inhibits the growth of CPPD crystals and affect the crystal phase of the developed CPPD crystals [78]. Based on this observation, a small clinical trial was designed to test the effect of magnesium supplementation on the CPPD crystals in vivo. However, the study showed no improvement in radiographic findings between the patients who were receiving magnesium compared to the ones receiving placebo [79]. Polyphosphates, such as sodium tripolyphosphate (Na5P3O10) and cyclic trisodium metaphosphate ((NaPO3)3), have also shown to be effective in vitro in dissolving CPPD aggregates formed in human menisci [80]. Polyphosphates act by removing the calcium ion from the pyrophosphate of the CPPD; a property, which could potentially be proven useful for controlling PPi levels in patients with hyperphosphatasia. To the best of our knowledge, however, no such trial has been undertaken yet. Alkaline phosphatase, an enzyme that is actively involved in the metabolism of PPi and it is known to interact with phosphate groups, has also shown the ability to dissolve CPPD crystals in vitro [81]. Moreover, because of its recognized role in hypophosphatasia [82], alkaline phosphatase has been proposed as another potential agent for curing CPP crystal deposition disease. To date, however, in contrast to other crystal-induced pathologies like gout, there is no effective pharmacological treatment for dissolving the deposited CPPD crystals in vivo. Treatment of CPP crystal arthritis is focused on management of acute attacks and chronic symptoms like inflammation and reduced mobility. Under this framework asymptomatic occurrence of CPP crystals, especially in the elderly, does not require treatment. Management of acute attacks or chronic pain can differ among individuals based on the specific patient’s characteristics and may require use of nonsteroidal antiinflammatory drugs, colchicine, or intra-articular long-acting glucocorticosteroids [53].

14.5 IN VITRO SYNTHESIS AND CHARACTERIZATION OF CPPD CRYSTALS 14.5.1 Synthesis of t- and m-CPPD Crystals Pyrophosphate compounds have been well studied since the early second half of twentieth century due to their importance to the chemical industry. Pyrophosphates have been widely used as fertilizers and up until today they are used as the main source of phosphate, calcium, or ammonium in plant nutrition. Brown et al., in 1963, conducted a comprehensive work on the chemical synthesis and characterization of 25 CPP compounds, among which many allomorphs of CPPD [33]. Here, we will only focus onto the monoclinic and the triclinic allomorphs of CPPD, also referred to as m-CPPD and t-CPPD respectively, as these are the only crystallographic phases detected in vivo. As such, studying the conditions under which these phases develop and dissolve is highly important in order to further our understanding of the CPP deposition disease.

14.5.1.1 Synthesis of m-CPPD Crystals As described by Brown et al., synthesis of m-CPPD can be achieved through the controlled transformation of amorphous CPP to crystalline Ca2P2O7.2H2O. For this method, a saturated solution of CaCl2 containing 1 g of K4P2O7 and 10 g of KCl in 60 mL of water is prepared and then further diluted to 100 ml with water. The diluted solution is left quiescent at 45  C for a period of time; usually a couple of weeks, during which a “gelatinous” precipitate of amorphous CPP forms and, under the appropriate conditions, then transformed into m-CPPD. The determinant factors for controlling the preparation of m-CPPD are the pH, the temperature, and the presence or absence of electrolyte. Precipitation in pure water favors the transformation to t-CPPD where lowering the pH below 6 or decreasing the temperature lead to the formation of CPPT [33].

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Twenty-five years later, Mandel et al., described a similar method for generating m-CPPD crystals through the transformation of amorphous CPP, this time, based on a different starting solution. For this method, an aqueous solution of magnesium chloride is prepared by the addition of 6.96 mL of 0.337 M MgCl2 in 106 mL of distilled water at 50  C. The solution is then heated at 80  C and 2 g of dihydrogen pyrophosphate (CaH2P2O7) are added under constant stirring. Stirring and heating continue for 15 min and during this period 8.25 mL of 2.33 M of calcium acetate is added. Finally, stirring is stopped, the stirring bar is removed, and the flask is kept at room temperature for 24 h until the amorphous calcium phosphate gel, which has been formed collapses and needle-shaped m-CPPD crystals are formed [83].

14.5.1.2 Synthesis of t-CPPD Crystals In the case of t-CPPD, the approach reported by Brown et al. is based on the transformation of an intermediate CDPP phase, synthesized by adding Ca(H2PO4)2$2H2O to 85% pyrophosphoric acid at 210  C, to t-CPPD. The transformation is taking place in water at room temperature in the course of a week during which crude prismatic crystals initially precipitate and then grow to form well-shaped t-CPPD crystals [33]. Mandel and coworkers slightly modified the above mentioned method by introducing moderate stirring during the addition of the CDPP. In brief, 1.10 g of CDPP was added into 250 mL of water under moderate stirring and stirring was continued until the solution was clear. The solution was kept quiescent for seven days by the end of which parallelogram-shaped t-CPPD crystals were formed. Importantly, the authors reported the formation of an unstable intermediate phase of orthorhombic calcium pyrophosphate dihydrate, which was not reported by Brown et al. [83]. Groves and coworkers reported a new synthetic procedure for the production of t-CPPD crystals. In this procedure, a CPP intermediate is first prepared by reaction of anhydrous potassium pyrophosphate and calcium chloride. Next, 8.16 g of CPP intermediate is added to about 850 mL water and 75 mL of 1.0 mol/L HCl added and the suspension stirred until the solid had dissolved. The solution was made up to 1 L with water. About 100 mL of this solution is placed in a 250 mL Erlenmeyer flask, 1.5 mL of 1.0 mol/L urea solution added and the flask placed on a steam bath for 3 h. Under these conditions, urea is hydrolyzed and the pH increases causing precipitation of t-CPPD crystals. Depending on the stirring of the solution, larger or smaller crystals were obtained. The above method improves the previously reported method by Brown since the yield is higher and does not include the preparation of CDPP, which involves the hazardous heating of phosphoric acid at 215  C [84].

14.5.2 In vitro Dissolution and Growth Properties of CPPD Crystals In vitro dissolution and growth of CPPD crystals were studied by Christoffersen et al. The rates of dissolution and growth in a pH range of 5e7 of t-CPPD microcrystals of acicular (needlelike) morphology were studied [85]. The rates of dissolution per unit area of acicular t-CPPD are roughly a factor of 2 faster than the corresponding rates for columnar t-CPPD. Growth of acicular t-CPPD also appears to be explained by the polynuclear mechanism, as previously found for growth of columnar t-CPPD. At low pH (4.5), the rates of growth per unit area of acicular and columnar t-CPPD are similar. At higher pH (5.5 and 6.5), the rates of growth per unit area of acicular t-CPPD are slower than corresponding rates for columnar t-CPPD. At constant pH, this effect increases as the supersaturation decreases. The main difference between the two morphologies is the edge length per unit area. The larger solution volume around edges may facilitate acicular crystal dissolution but lead to inhibition of acicular growth by chelation of pyrophosphate to calcium ions blocking normal growth [34,85].

14.5.3 Characterization of t- and m-CPPD in Pathological Deposits Identification of CPPD crystals pathological deposits such as in synovial fluid and joint tissue is of great importance for the clinicians since it can increase the knowledge on the mechanism of formation and improve therapeutic and prevention approaches [86]. Two comprehensive reviews of some of the most important analytical tools employed in the detection of calcium phosphate crystals in synovial fluids and joint tissues are provided in references [87] and [88]. During the early days, PLM was widely used in the clinical practice to identify CPPD crystals in pyrophosphate arthropathy. The use of PLM provided clinicians a simple, cheap, and fast way for identifying this type of crystals based on their birefringence properties. However this method has been criticized and it is now well accepted that PLM lacks both sensitivity and specificity when it comes to the identification of CPPD [86,89]. During the last decades, new instrumental analytical techniques have been implemented in the characterization of crystals developed during OA in the synovial fluids or the articular tissues. These techniques, summarized in Table 14.5

386 Mineral Scales and Deposits

TABLE 14.5 Available Methodology for Articular Crystal Identification Type

Advantages

Disadvantages

Light microscopy

Inexpensive, widely available, may pick up more calcium pyrophosphate dihydrate crystals

Inaccurate, nonspecific

Polarizing light microscopy

Inexpensive, widely available

Poorly reproducible

Light microscopy with special stains

Inexpensive, widely available, can identify basic calcium phosphate crystals

Nonspecific, false positives

X-ray diffraction

Accurate

Requires drying of samples, poor resolution of small or dilute samples

Fourier transform infrared spectroscopy

Accurate

Expensive, can be misinterpreted, water interferes

Raman spectroscopy

Accurate, no water interference

Fewer available standard spectra, expensive

Transmission electron microscopy

Can be used with electron diffraction, small sample size

Complex, expensive

Scanning electron microscopy

Small sample size

Complex, expensive, relies on morphology

Atomic force microscopy

Little sample preparation, small sample size, research tool

Not widely available, expensive

Magnetic resonance imaging

Can be done in situ

Inaccurate, nonspecific

Adapted and modified from [87] and reprinted with permission.

along with some of their advantages and disadvantages, had a significant impact on the way characterization is done nowadays. XRD and vibrational spectroscopic techniques such as the Fourier transform infrared spectroscopy (FTIR) and Raman spectroscopy are now used to provide accurate information about the nature and composition of the pathological mineral deposits. These methods can be applied to samples after minimal sample preparation, but they require stand-alone (benchtop) instruments, which are not widely available in the clinical routine. A comprehensive review on the use of such techniques and their potential in supporting medical diagnostics is beyond the scope of this chapter, however, detailed reviews in which the reader could refer are available in the literature (e.g., Petrich [90]). We have recently published a study in which we used a combination of the aforementioned techniques, i.e., XRD and FTIR, for the characterization of CPPD deposits on human menisci obtained from osteoarthritic patients during total knee arthroplasty operations. The identification of the nature and crystal structure of the deposits was performed by comparing the experimental XRD diffractograms of the tissue’s depositions with the Joint Committee on Powder Diffraction Standards (JCPDS) card or standard synthetic crystals as well as by studying their IR-active vibrational modes [62]. Another nondestructive technique, which is used nowadays for the physicochemical characterization of pathological deposits is Raman microspectroscopy [91e93]. The technique has been successfully applied in many cases to study crystals in pathological samples from patients with CPP crystal deposition disease. A recent example is the use of Raman microspectroscopy for the identification of pathological calcifications in the human eye sclera [91]. In this case, Chen et al., used a 30 mW green (532 nm) solid state laser and by assignment of the most prominent bands revealed the coexistence of m-CPPD and hydroxyapatite in the calcified plaque. A novel and more powerful vibrational analysis technique, which expands the capabilities of the current ones is Synchrotron Radiation-based Fourier Transform Infrared (SR-FTIR) spectromicroscopy. SR-FTIR spectromicroscopy uses extremely bright synchrotron radiation as a light source, which allows chemical mapping with high spatial resolution. However, the use of such instrumentation requires national scale facilities and is very expensive. Thus, SR-FTIR spectromicroscopy can only be used for research, and not clinical, applications. Rosenthal et al., used SR-FTIR spectromicroscopy to identify calcium phosphate crystals, including CPPD, which had been formed both in vitro and in vivo [94].

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14.5.4 In vitro Model Systems for the Study of Pathological Cartilage Calcification In vitro models have been developed by many researchers in order to study the conditions under which CPPD crystals are formed in an effort to further our understanding of the pathogenesis of CPP crystal deposition disease. These models involve crystal growth from solutions and gels and both have contributed significantly to the current knowledge of CPPD chemistry. As with all models, though, there are also weaknesses when they are used to simulate the physiological medium. For example, in the case of crystal growth from solutions no organic matrix or cells are present while in the case of growth in gels it is difficult to monitor crystal growth or separate and quantify the resulted crystals [95].

14.5.4.1 Growth in Gels Harries and coworkers have grown CPPD crystals in gelatin and polyacrylamide gels in an effort to simulate the in vivo growth. They suggested that very careful studies should be made since gelatin and polyacrylamide gels showed considerably different responses on CPPD crystal growth. It has been shown that a low calcium concentration and an alkaline pH favor the growth of t-CPPD crystals in gelatin gels. However, using polyacrylamide gels they found that the pH within the gel is stable and the temperature of the growth medium is regulating the nature of grown CPPD crystals [96]. Growth of CPP crystals in native collagen gels has been performed by Hunter et al., CPP crystals were grown by diffusion of calcium ions into type I collagen gels doped with sodium pyrophosphate. Since proteoglycans from older individuals have a higher content of keratan sulfate and lower content of chondroitin sulfate the effect of these two glycosaminoglycans was evaluated. Comparison of the inhibition of direct formation of CPPD by the two glycosaminoglycans present in cartilage proteoglycan showed that chondroitin sulfate is a more potent inhibitor than keratan sulfate [97].

14.5.4.2 Growth in Solutions Crystal growth of CPPD was studied in aqueous solutions over a range of calcium chloride and sodium pyrophosphate concentrations to determine the ionic conditions under which t- or m-CPPD is formed (Cheng 1979). By varying PPi and Pi concentrations, it was found that Pi/PPi ratio is an extremely important determinant of the crystal product formed. When the [Pi]/[PPi] ratio is less than three, formation of CPPD is taking place, while calcium hydroxyapatite forms at [Pi]/[PPi] ratio greater than 100. In another study, it was found that magnesium affects the polymorph of CPPD formed. Low [Mg2þ] and [PPi] concentration favored the formation of t-CPPD, whereas at higher [Mg2þ] and [PPi] formation of m-CPPD occurs [98]. Crystal growth experiments in buffered solutions using radioactive calcium to monitor crystal formation showed that orthorhombic CPPT formed in the absence of Mg2þ and amorphous in the presence of physiological concentrations of Mg2þ. The above mentioned phases formed after 3 days incubation, while longer incubation of a month or more in the presence of both calcium and magnesium allows the slow formation of crystals of the monoclinic type, followed by slow transition to the triclinic form. This observation can have a physiological significance since t-CPPD, which is the most common crystal form in vivo, is probably the final transition state of different crystal forms [37].

14.5.4.3 Growth in Media Containing Cells, Tissues or Matrix Vesicles These models have contributed substantially to our knowledge of CPPD formation in vivo. Growth of CPPD has been achieved in media containing intact adult porcine articular cartilage and monolayers of chondrocytes while ATP was used as the source of PPi. It has been shown that hydrolysis of ATP to Adenosine Monophosphate (AMP) and PPi is necessary for the CPPD formation. Formation and that such minerals mainly concentrate in articular cartilage vesicles in the perichondral area [99]. The articular cartilage vesicle fraction of porcine hyaline cartilage induced CPPD formation after 24 h in physiologic salt solution containing 1 mM ATP [100]. Articular cartilage MVs from knee joints of normal human adult articular cartilage were examined for protein and enzyme content and biomineralizing capacity in comparison to MVs derived from human osteoarthritic cartilage. It has also been shown that isolated MVs from normal cartilage generate pathologically relevant crystal phases (CPPD and apatite) in vitro. This implies that matrix integrity and substrate availability may be crucial factors in the control of pathologic biomineralization [101]. New insights into the potential pathogenic mechanisms for CPP formation can be obtained by developing models using scaffolds, which have been developed for use in cartilage tissue transplantation [95].

14.5.5 Inhibitors Inhibitors are compounds, which slow or prevent the formation of crystal nuclei or retard the crystal growth. The role of naturally occurring inhibitors of CPPD crystals is of high importance for our understanding of the CPPD crystal-related disease as well as for planning and developing new strategies to treat them.

388 Mineral Scales and Deposits

For this purpose, several in vitro studies have been conducted evaluating the inhibition properties of various natural and synthetic compounds under supersaturation conditions. These studies looked at the inhibition of crystal growth of seed crystals in solutions under low supersaturation conditions or at the inhibition of the spontaneous precipitation of CPPD crystals in solution at a high degree of supersaturation. In the first case, inhibitions are associated with the absorption of the compound onto the surfaces of the growing crystals, thereby blocking any potential growth sites and preventing further incorporation of lattice ions. In the second case, the inhibitors bound todor complex withdthe free ions of the solution phase leading to lower ion supersaturations and lower crystal nucleation and growth rates. One of the naturally occurring compounds, which effectively inhibits CPPD formation and growth is phosphocitrate (PC). PC was originally found in rat liver mitochondrial extracts and crab hepatopancreas and was described to be able to prevent uptake and crystallization of calcium phosphate in mitochondria in vivo [102]. Later, in articular cartilage models and articular cartilage vesicles was also proven to be an effective inhibitor of CPPD [103]. PC is a phosphorylated carboxylic acid, which exhibits excellent affinity to the calcium ions located on the surface of these crystals. Its inhibitory activity is mainly attributed to ionization of the hydroxyl and carboxylic groups at neutral to slightly alkaline pH and from the stereospecific interaction between PC and some of the faces of the CPPD crystal [104,105]. Furthermore, chelation between citrate and Ca2þ results in the reduction of free Ca2þ ions in the solution and therefore the inhibition of during spontaneous precipitation of CPPD [106]. The role of proteoglycans on CPPD inhibition has also been studied by means of crystal growth experiments in the presence of model carboxylate-containing compounds in solutions supersaturated with t- and m-CPPD. Spontaneous and seeded growth experiments showed that monocarboxylates (acetate, glucuronate) have little inhibitive effect, while progressively greater inhibition was found with dicarboxylate (malate) and tricarboxylate (citrate) indicating that the arrangement of carboxylate sulfate, and ligands of the proteoglycan is more important than the inhibitory effect of individual ligands. These observations can be attributed to the orientation of some carboxyl and sulphate groups, on surface calcium ions of CPPD nuclei or crystals.

ACKNOWLEDGMENTS We are grateful to Dr. Sofia Michopoulou for the fruitful discussions during the writing of this manuscript and for text editing-proofing of the final manuscript.

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