Genetic and metabolic aspects of the pathogenesis of osteoarthritis

The role of mechanical factors in the pathogenesis of osteoarthritis is unquestionable, but there are convincing data that some forms of osteoarthritis are inherited according to the laws of Mendel. Hereditary osteoarthropathies can be divided into:

• primary generalized osteoarthrosis (PGOA),
• crystal associated arthropathies,
• premature osteoarthritis due to hereditary osteochondrodysplasia.

In 1803 W. Heberden described "slightly dense knots, the size of a small pea" on the back surface of the distal interphalangeal joints of the hands. This feature, according to the author, distinguishes osteoarthritis from other joint diseases, including gout. J. Hayagarth (1805) expanded the clinical description of Geberden's nodes, noting their frequent association with arthrosis of other localizations. Bouchard further described similar nodes on the dorsal surface of the proximal interphalangeal joints of the hands. Using the term "Heberden and Bushard nodes", W. Osier shared "hypertrophic arthritis" and "deforming arthritis" (1909). In 1953, RM Stecher and H. Hersh discovered the distribution of Heberden's nodes among family members and concluded that they are inherited in an autosomal dominant manner. Following the discovery of RM Stecher and H. Hersh, the studies revealed the association of Geberden and Bushard nodes with degenerative lesions of other joints. Based on the current clinical examination and HLA-typing, JS Lawrence (1977), JS Lawrence and coauthors (1983) suggested the presence of polygenic inheritance, rather than a defect of a single gene.

The phenotypic spectrum of hereditary osteoarthritis varies widely from mild forms that manifest clinically only after reaching late adulthood, to very severe forms that manifest in childhood. Traditionally, all these forms have been classified as secondary osteoarthritis. It is now known that the cause of some of these phenotypes is the mutation of genes encoding macromolecules of ECM of the articular cartilage, which violates the integrity of the cartilage matrix, as well as the regulation of chondrocyte proliferation and gene expression. These hereditary diseases represent a certain subgroup of osteoarthritis, which differs from secondary osteoarthritis.

Differences between hereditary and secondary osteoarthritis (according to Williams CJ and Jimenez SA, 1999)

	Hereditary osteoarthritis	Secondary osteoarthritis
Etiology	Mutation of genes expressed in articular cartilage	Various hereditary and acquired diseases
Pathogenesis	Damage to structural or functional components of articular cartilage	Secondary manifestations of the disease, not always affecting only the articular cartilage
Treatment	Possible gene therapy for correction of gene defect	Treatment of underlying disease

Chondrodysplasia / osteochondrodysplasia - a group of clinically heterogeneous diseases characterized by growth and development anomalies of articular cartilage and growth plate. Some HD / OXD lead to early development of osteoarthritis, clinically characterized by severe course. Among them, the following diseases can be distinguished:

• spondyloepiphysial dysplasia (SED),
• syndrome Stickler,
• dysplasia of Knish,
• multiple epiphysical dysplasias (MED),
• metaphysical chondrodysplasia (MHD),
• some oto-spondylo-metaepiphysial dysplasias (OSMED).

Hereditary dysplasia characterized by early onset of osteoarthritis (according to Williams CJ and Jimenez SA, 1999)

Disease	Locus	Inheritance type	The mutated gene	Mutation type
Early OA with late onset of SED (SAR) *	12q13.1-q13.2	HELL	COL 2 A,	Substitution of base, insertion, deletion
Syndrome of Stickler (STL1)	12q13.1-q13.2	HELL	COL2A1	Replacement of the base, insertion
Syndrome of Stickler (STL2)	6p21.3	HELL	COLA	Insertion, Deletion
Stickler Syndrome	1p21	HELL	COLA	Replace the base
Wagner's syndrome	12q13.1-q13.2	HELL	COUA,	Replace the base
OSMED	6p21.3	AR	COLA	Replace the base
Marshall Syndrome	1p21	HELL	COLA	Insert
Book dysplasia	12q13.1-q13.2	HELL	COLA	Insertion, Deletion
M3fl (EDM1)	19p13.1	HELL	COMP	Replace the base
MED (EDM 2)	1р32.2-рЗЗ	HELL	COLA	Insert
MCD Schmid (MCDS)	6q21-q22.3	HELL	COLA	Substitution of base, deletion
MHJ Jansen (MCDJ)	Зр21.2-р21.3	HELL	PTHR,	Replace the base

* In brackets are the symbols of the locus; AD - autosomal dominant; AR is autosomal recessive.

Spondyloepiphysial dysplasia

Spondyloepiphysial dysplasia (SED) includes a heterogeneous group of diseases with an autosomal dominant type of inheritance, characterized by an abnormal development of the axial skeleton and severe changes in the epiphyses of long tubular bones, often causing dwarfism. Often, SED clinically difficult to proceed, accompanied by a shortening of the body and less limbs.

In forms of SED that manifest at a later age, the phenotype is often little changed and may not appear clinically until adolescence, when severe osteoarthritis develops. Deformation of the lumbar spine may be manifested by a narrowing of the intervertebral discs, platipondylia and insignificant kyphoscoliosis. Also, there are anomalies of the epiphyses in the peripheral joints and early degenerative changes in them. The most constant sign of lesion of peripheral joints is the flattening of the articular surfaces of the ankles and knee joints, as well as the flattening of the intercondylar groove of the femur. Often there are anomalies of the head and neck of the femur with the development of osteoarthritis of the hip joint, which manifests in adolescence.

Due to the fact that type II collagen is the main component of the HCM of hyaline cartilage, it is suggested that the cause of the EDS is the COL1A gene encoding it. The first description of the genetic link between the phenotype of early osteoarthritis associated with the late manifesting EDS and the procollagen II gene of type COL ₂ A dates back to 1989 and 1990. The first report on the COL ₂ A mutation in relatives with early osteoarthrosis associated with a late manifesting SED , concerned the replacement of the base Arg519> Cys. To date, four families with similar mutations have been identified. In members of another family with early OA and a readily flowing SED, a substitution of the Arg75> Cys base was found, although the SED phenotype in the members of this family is not similar to the family phenotype, with arginine replaced by cysteine at position 519. Other mutations COL ₂ A-Gly976> Ser, Gly493> Ser. J. Spranger and co-authors (1994) used the term "type 11 collagenopathy" to describe hereditary cartilage tissue diseases with a primary mutation of the procollagen II gene of type COL1A.

Classical form of the syndrome of Stickler

It was first described in 1965 by GB Stickler and co-authors, who called it hereditary arthro-ophthalmopathy. The GB syndler described by the syndrome was characterized by damage to the organ of vision and a severe degenerative joint disease, which usually develops in the third or fourth decade of life. This is an autosomal dominant disease, the prevalence of which is approximately 1 per 10 thousand newborns. The clinical picture of the disease includes myopia, progressive deafness, cleft palate, lower jaw hypoplasia (Pierre-Robin's anomaly) and epiphysic hypoplasia. In the neonatal period on the radiographs of patients with the syndrome of the Stickler, there are enlarged epiphyses, mainly the proximal femoral and distal tibia. In the process of growth, dysplasia of the epiphyses develops, which manifests itself in the irregularity of the ossification of the epiphyses and subsequent degenerative changes.

Since COL ₂ A is expressed in the articular cartilage and vitreous body of the eyeball, the appearance of the syndrome of Stickler was associated with the pathology of this gene. However, a survey of several families with the syndrome of Stickler showed that not all families have the disease associated with COL ₂ A. This form of the disease is called type I syndrome of the Stickler (symbol of the locus STL1).

The spectrum of clinical manifestations of the syndrome of the Stickler varies widely, at present several phenotypes have been identified. Among them - Wagner syndrome, which is characterized by the prevalence of the defeat of the eyeball; OA in Wagner's syndrome does not actually develop, although the mutation of the COL ₂ A gene , (substitution of the Gly67> Asp base) is revealed in the patients . It remains unclear why such a mutation COL compromises only the function of the vitreous body and does not affect the hyaline cartilage.

Another form of the syndrome of the Stickler is the so-called Dutch variant; it is characterized by all the classic manifestations of the syndrome except for the damage to the organ of vision. HG Brunner et al (1994) showed that Dutch Stickler syndrome phenotype associated with mutation COL gene, A ₂ : dominant mutation is a deletion of 54 base pairs followed by a deletion of exon M.Sirko-Osadsa et al (1998) reported another family described unrelated to previous authors, with similar phenotype and gene mutation COL, and a ₂ (deletion of 27 base pairs), which supports data HG Brunner et al (1994). This variant is called the II type of syndrome of the Stickler (symbol of the locus STL1).

Recently, the third locus of the syndrome of Stickler was found in family members with vitreous and retinal pathologies, which phenotypically differ significantly from the changes observed in the "classical" version of the syndrome. Representatives of this family found a mutation of the gene COL2A | (substitution of bases Gly97> Val). Of course, to confirm the findings of AJ Richards and co-authors, new descriptions of cases of such phenotype and genotype of the syndrome of Stickler are needed.

For a long time the issue of the nosological connection of the Marshall syndrome and the classical version of the syndrome of Stickler was discussed. Now Marshall syndrome is classified as a separate phenotype mainly due to a more pronounced deformation of the facial skeleton, although peripheral joint damage is similar to that of Type I syndrome. In Marshall syndrome, osteoarthritis of the knee joints and the lumbosacral spine begins after 30 years. The cause of the syndrome is a mutation of the collagen IX gene of type COL _n A1.

[1], [2], [3], [4], [5], [6]

OSMED

This phenotype was described in a Dutch family whose members degenerative joint changes resembling osteoarthritis appeared during adolescence and affected mainly the hip, knee, elbow and shoulder joints; Also, peculiar facial features, lumbar lordosis enhancement, interphalangeal joints increase, deafness, but no abnormalities of the visual organ (Vikkula M. Et al., 1995). The researchers found a mutation of the gene encoding a _2- chain of collagen II type COL ,, A ₂.

Book dysplasia

It is characterized by shortening of the trunk and extremities, flattening of the face and back of the nose, exophthalmos and severe anomaly of the joints. In patients with Knin's syndrome, joints, usually large from birth, continue to increase in childhood and early adolescence. They also often can detect myopia, hearing loss, cleft palate, clubfoot; the majority of patients develop early severe degenerative changes, especially expressed in the knee and hip joints. On the roentgenograms of the spine, a flattening and considerable elongation of the vertebral bodies, platipondylia, are detected. Long tubular bones are deformed as a dumbbell, ossification of epiphyses is slowed down. In the joints of the hands, the epiphyses are flattened and joint joints are narrowed. Articular cartilage is soft, its elasticity is reduced; histologically, large cysts (a symptom of "Swiss cheese") are found in it. The cause of Knyst syndrome is a mutation of the procollagen II gene of the COb2A1 type.

[7], [8], [9], [10], [11], [12], [13], [14]

Multiple epiphysial dysplasias (MED)

A heterogeneous group of diseases characterized by an anomaly in the development of growth plates of long tubular bones, as well as with early (manifesting in childhood) severe osteoarthritis affecting both axial and peripheral joints (most often knee, hip, shoulder and hand joints). Clinically, MEDs are manifested by pain and stiffness in the joints, a change in gait. Patients with DER also have minimal changes from the vertebral column (various degrees of flattening of vertebral bodies), sometimes the spine is intact. Low growth of patients is also characteristic, although dwarfism develops rarely. The organ of vision is not affected. DERs include several variants, for example the phenotype of Ferbanks and Ribbing.

MEDs are inherited in an autosomal dominant type with varying degrees of penetrance. Since the distinctive feature of the MED is the anomaly of the growth plate of the epiphyses, it has been suggested that the cause of these dysplasias is the defect of the genes encoding the growth cartilage macromolecules. It turned out that at least three loci are associated with the DER phenotype. Research E.J. Weaver et al. (1993), JT Hecht et al. (1992) excluded the genes of type II and VI collagen, proteoglycan core protein and cartilage connective from the list of "culprits" of EDR. JT Hecht et al. (1993), R. Oehelmann et al. (1994) found a link between EDR, as well as the clinically similar pseudochondroplasia syndrome, and the pericentromeric region of the 19th chromosome. Subsequent studies identified a mutation of the gene encoding the cartilage oligomeric matrix protein (OMPC) in three patients with EDR (locus symbol EDM1). Since all three mutations occurred in the region of the gene that codes for the calcium-binding domain of OMPH, it is probably the calcium-binding function of this protein that is inherent in the normal development of the cartilage of the growth plate.

MD Briggs and co-authors (1994) reported a family from Holland whose MED-phenotype was associated with the site of the first chromosome containing one of the COL1A1 type IX collagen genes (symbol of the EDM ₂ locus ). It is noteworthy that the mutation found was the first evidence of the role of type IX collagen localized on the surface of collagen II fibrils in maintaining the integrity of the hyaline cartilage. M. Deere and co-authors (1995) showed that the phenotype of the Ferbanks is not genetically associated with either the EDM locus or the EDM ₂ locus , which confirmed the heterogeneity of the MED.

Metaphysical chondrodysplasia (MHD)

Heterogeneous (described more than 150 types) group of hereditary hyaline cartilage diseases, which are clinically manifested by early osteoarthritis. MCH are characterized by changes in metaphyseal bones. Clinically, they are manifested by low growth, shortening of limbs, curvature of the legs, "duck" gait. Also, patients with MHD show signs of damage to other systems (eg, the immune and digestive systems). The disintegration of the cartilage of the growth plate is observed, which is histologically manifested by clusters of proliferated and hypertrophied chondrocytes surrounded by thickened septa and a disorganized matrix, as well as the penetration of uncalcified cartilage into the subchondral bone.

The syndromes of Jansen, Schmid and McCusick are the most well-studied MHD. They are similar in features of skeletal anomalies, but differ in severity (Jansen syndrome-McKusick syndrome-Schmid syndrome). The most common is Schmid syndrome (the symbol of the MCDS locus), which is inherited by the autosomal dominant type. X-ray syndrome is manifested by coxa vara, shortening and curvature of tubular bones, cup-like deformation of metaphyses (more pronounced in the proximal than in the distal femur). The most pronounced changes are observed in growth plates of long tubular bones.

At least 17 different mutations of the X type collagen gene are described in patients with Schmid syndrome. Collagen X type is expressed in hypertrophied chondrocytes of growth plates and, possibly, participates in ossification processes. Thus, the mutation of the collagen-encoding X type of the COb2A1 gene is the most likely cause of Schmid's syndrome.

Children with Jansen syndrome have hypercalcemia, as well as an elevated level of phosphate in the urine, a decrease in the level of parathyroid hormone (PG) and PG-linked peptide. With the anomaly of the latter, probably, the emergence of the syndrome of Jansen. In 1994, AS Karaplis and co-authors published the results of the original study. After the gene that encodes the PG-linked peptide in the stem cells of the mouse embryos is destroyed, the mice deficient for this allele die immediately after birth. They had an anomaly in the development of the subchondral bone, a violation of the growth of the cartilage, and a decrease in the proliferation of chondrocytes. In 1995, E. Schipani and co-authors reported a heterozygous mutation of the PG-linked peptide receptor gene in a patient with Jansen syndrome. The mutation consisted in replacing the base of Gys223> Arg, which led to the accumulation of cAMP; this means that the amino acid histidine at position 223 plays a crucial role in signal transmission. Later E. Schipani and co-authors (1996) reported three other patients with Jansen syndrome, two of whom had a similar mutation, and the third had a substitution TruA10> Pro .

Primary generalized osteoarthritis 

The most common hereditary form of osteoarthritis is the primary generalized osteoarthrosis (PGOA), which was first described as a separate nosology of JH Kellgren and R. Moore in 1952. Clinically, the primary sites of generalized osteoarthrosis are the appearance of the Bushard and Geberden nodes, the polyarticular lesion. Primary generalized osteoarthritis is characterized by an early onset of manifestation of osteoarthritis and its rapid progression. Radiologically primary generalized osteoarthritis does not differ from non-hereditary osteoarthritis. Although the question of the etiopathogenesis of primary generalized osteoarthritis is still debated, the studies demonstrate the important role of the hereditary predisposition in the onset and progression of primary generalized osteoarthrosis.

Thus, JH Kellgren and co-authors (1963) discovered the knots of Busarai Geberden in 36% of male relatives and 49% of female relatives, whereas in the general population these figures were 17 and 26%, respectively. In persons with primary generalized osteoarthrosis, HLA A1B8 haplotype and MZ isoform of a1-antitrypsin are more often detected. In a classic study involving twins, TD Spector and co-authors (1996) performed radiographs of knee joints and arm joints in 130 single and 120 twin female twins for the presence of changes characteristic of osteoarthritis. It turned out that the concordance of X-ray signs of osteoarthritis of all localizations was 2 times higher in monozygotic twins as compared with the bipartisans, and the contribution of genetic factors ranged from 40 to 70%. In the study of nodular osteoarthritis conducted by GD Wright and co-authors (1997), the early onset of the disease, a high severity and a negative correlation between the onset of illness in patients and the age of their conception by parents were demonstrated.

Among the crystal-associated arthropathies, the deposition of crystals of uric acid and calcium-containing crystals in the joint cavity has a family predisposition.

Hereditary crystal-associated arthropathy (according to Williams, C.J. And Jimenez SA, 1999)

Disease	Locus	Inheritance type	The mutated gene	Mutation type
Gout (HPRT) *	Xq27	Associated with the X chromosome	HPRT1	Substitution of base, deletion
Gout (PRPS)	Xq22-q24	Associated with the X chromosome	PRPS1	Replace the base
Primary pyrophosphate arthropathy (CCAL1)	5p15.1-p15.2	HELL	?	?
Pyrophosphate arthropathy associated with the early onset of 0A (CCAL2)	8q	HELL	?	?

* In brackets are the symbols of the locus; AD is autosomal dominant.

In 1958, D. Zintann S. Sitaj presented clinical descriptions of the pathology, which they called "chondrocalcinosis" in 27 patients. Most patients belonged to five families, which indicated a hereditary component in the etiopathogenesis of the disease. Later, D. McCarty and JL Hollander (1961) reported two patients who suspected gout with the deposition of non-permanent crystals in the joint cavity. X-ray examination revealed an abnormal calcification of the hyaline cartilage of many joints.

Radiologically, the disease of deposition of calcium pyrophosphate crystals of dihydrate, or pyrophosphate arthropathy, resembles sporadic OA, but it often affects joints that are not typical for common forms of osteoarthrosis (eg, metacarpophalangeal, navicular-ray, patello-femoral part of the knee joint). With pyrophosphate arthropathy, cysts of the subchondral bone are more often formed. Although in most cases, chondrocalcinosis occurs before the manifestation of secondary osteoarthritis, in some individuals the disease can begin as idiopathic osteoarthritis, which is accompanied by metabolic disorders (hemochromatosis, hyperparathyroidism, hypomagnesemia, etc.).

Most likely, structural changes in ECM of articular cartilage induce deposition of calcium pyrophosphate crystals of dihydrate. A.O. Bjelle (1972, 1981) found a decrease in the collagen content and fragmentation of collagen fibers in the middle zone of the articular cartilage matrix of family members from Sweden with pyrophosphate arthropathy. Since these sections did not contain crystals, the authors suggested that the described matrix anomaly may predispose to their deposition and the development of degenerative changes in the joints. Based on the study of sporadic cases of pyrophosphate arthropathy K. Ishikawa and coauthors (1989), I. Masuda and co-authors (1991) concluded that the cause of chondrocalcinosis is a mutation of genes encoding VKM proteins. CJWilliams et al. (1993), AJ Reginato et al. (1994) found a heterozygous mutation COL ₂ A (substitution of bases Argl5> Cys) in large family members with a clinical phenotype of severe early osteoarthritis with ankylosing, late development of spinal falciphysia and chondrocalcinosis of hyaline and fibrous cartilage. However, it turned out that the members of this family had secondary chondrocalcinosis in relation to OA.

It was also suggested that the formation of crystals is promoted by the inorganic components of ECM. For example, hypomagnesemia causes the development of chondrocalcinosis by inhibiting the pyrophosphatase enzyme, which in turn reduces the dissolution of the crystals. In the synovial fluid of patients with pyrophosphate arthropathy, an increased content of inorganic phosphates was found. This and other observations made it possible to suggest that in patients with pyrophosphate arthropathy there is a local disturbance in the metabolism of pyrophosphates. The enzyme of nucleoside triphosphate pyrophosphohydrolase, which probably participates in the formation of pyrophosphate crystals in the zone of their deposition in the ECM, is described. In sporadic cases of pyrophosphate arthropathy, an increased content of this enzyme was found, however, in family forms of the disease such an anomaly was not observed (Ryan LM et al., 1986). Nevertheless, in the cultivation of fibroblasts and lymphoblasts in patients with familial pyrophosphate arthropathy, an increase in the content of inorganic phosphates was found, which also confirms the assumption of the role of disturbances in the local metabolism of pyrophosphates in the pathogenesis of the disease.

In recent years, attempts have been made to identify genes that are "guilty" in the occurrence of family cases of pyrophosphate arthropathy. Thus, analysis of the genetic material obtained from members of a large family with pyrophosphate arthropathy (Maine, USA), in which chondrocalcinosis developed secondary to severe fast progressive non-dilatative osteoarthritis, excluded the association of the disease with the locus COL ₂. However, the authors of this study found a link between the studied phenotype of pyrophosphate arthropathy and the locus located on the long arm of the 8th chromosome (the symbol of the CCA locus). AG Hughes et al (1995) found a link between the phenotype of primary chondrocalcinosis in a UK family and the CCAL1 locus, which is located on the short arm of the 5th chromosome in the 5p15 region. According to CJ Williams and co-authors (1996), the locus CCAL1 from members of the family from Argentina with pyrophosphate arthropathy was located somewhat proximal than in the previous case - in the region 5p15.1. A similar genotype was found in family members from France.

Thus, the data of the described studies indicate that the family form of pyrophosphate arthropathy is a clinically and genetically heterogeneous disease, caused by mutations of at least three different genes.