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Progressive ankylosis in mice.

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1390
PROGRESSIVE ANKYLOSIS IN MICE
An Animal Model of Spondylarthropathy
I. Clinical and Radiographic Findings
MAREN L. MAHOWALD, HOLLIS KRUG, and JOEL TAUROG
To determine its similarity to human spondylarthropathies, we studied murhe progressive ankylosis, a
spontaneously occurring disorder of joints in mice.
Clinically, peripheraljoints were inflamed initially, then
became ankylosed in a predictable sequence from distal
to proximal. Forefeet were involved before hindfeet.
Axial joint involvement produced severe spinal ankylosis. Extraarticular manifestations included balanitis and
crusting skin lesions. Radiographically, bony erosions
and calcification of articular and periarticular tissues
were extensive, and vertebral syndesmophytes produced
a “bamboo” spine. We conclude that progressive ankylosis is a systemic disease with many clinical and radiographic similarities to human spondylarthropathies,
and it may represent a useful animal model for the study
of the human diseases.
scribed noninflammatory hyperplasia of synovial tissues, fibrosis, and calcification around peripheral and
axial joints in mice with this disorder. Hakim et a1 (2),
studying tissues from younger animals with progressive ankylosis (ank/ank animals), found prominent
inflammation in synovium consisting of “proliferative
synovitis” and periarticular cysts filled with “amorphous debris, large mononuclear cells, and scattered
polymorphonuclear leukocytes.” Interestingly, they
also found calcium hydroxyapatite (basic calcium
phosphate [BCP]) crystals in synovial fluid (SF). Hakim and coworkers’ finding of inflammatory synovitis,
coupled with the suggestion by Sweet and Green that
MPA resembled ankylosing spondylitis (AS), prompted us to examine this genetic disorder for similarities
to the human spondylarthropathies.
Murine progressive ankylosis (MPA) is a recessive mutation that progressively decreases mobility in
peripheral and axial joints. Sweet and Green (1) de-
MATERIALS AND METHODS
Presented in part at the 49th Annual Meeting of the American Rheumatism Association, Anaheim, CA, June 1985.
From the Departments of Medicine at the Minneapolis
Veterans Administration Medical Center, University of Minnesota
School of Medicine, Minneapolis, Minnesota, and the University of
Texas Health Science Center, Dallas, Texas.
Supported by the Veterans Administration and by a grant
from the Minnesota Chapter of the Arthritis Foundation.
Maren L. Mahowald, MD: Associate Professor, Minneapolis VA Medical Center; Hollis Krug, MD: Fellow in Rheumatology,
Minneapolis VA Medical Center; Joel Taurog, MD: Assistant Professor, University of Texas Health Science Center.
Address reprint requests to Maren L. Mahowald, MD,
Rheumatology Section, Minneapolis VA Medical Center, 54th and
48th Avenue So., Minneapolis, MN 55417.
Submitted for publication September 9, 1987; accepted in
revised form July 8, 1988.
Arthritis and Rheumatism, Vol. 31, No. 11 (November 1988)
Mice. We obtained 8 breeder pairs, heterozygous for
the recessive skeletal mutation progressive ankylosis on a
C3B6 hybrid background, from Jackson Laboratories (Bar
Harbor, ME). The pairs were caged separately, and litters
were weaned at 3 weeks of age. After 2 weeks of age, ears
were marked, and entire litters were examined twice weekly
according to a protocol based on the initial description of this
mutation (1). These studies were performed using established guidelines (3).
Clinical evaluation. The following parameters were
clinically evaluated: forepaw grasp of a wire grid; ability to
cling to the inverted wire grid; gait; thorax flexibility; spinal
mobility; swimming ability; and appearance of eyes, skin,
genitals, and peripheral and axial skeletal joints with respect
to erythema and swelling, joint deformity, and range of
motion.
Changes in joint mobility, determined by observation
and passive manipulation of the joints, were scored on a
MURINE PROGRESSIVE ANKYLOSIS
scale of 0-3, where 0 = normal range of motion; grade 1 =
80-90% of normal; grade 2 = 40-60% of normal; and grade 3
= 520% of normal. Swelling was graded on a scale of 0-3 (0
= none; 1 = minimal; 2 = moderate; 3 = extensive).
Strength of forepaw grasp of a wire grid was graded on a
scale of 0-3, where 0 = normal; grade 1 = slight weakness
with tail pull; grade 2 = unable to resist tail pull; and grade
3 = unable to grasp the grid. Inverted grid walking (cling),
which requires strong grasping ability of both forepaws and
hindpaws, was evaluated on a scale of 0-3, where 0 =
normal; grade 1 = able to grasp the grid as it was turned
upside down but fell off when the grid was shaken; grade 2 =
fell off the grid as soon as it was turned upside down; and
grade 3 = unable to hold on as the grid was raised to the
vertical position. Ability to swim was graded as follows: 0 =
normal swimming ability; 1 = able to swim for an extended
but decreased period of time, with abnormal body position in
the water; 2 = able to swim for a brief period of time only (2
or 3 minutes) before allowing the face to become wet; and 3
= unable to swim for any length of time because of inability
to keep the nose above water.
Chemical and immunologic determinations. Serum
chemistries and rheumatoid factor determinations were performed by the Minneapolis Veterans Administration Medical
Center (VAMC) clinical laboratories. Albumin, calcium, and
phosphorous were determined using Worthington Demand
technology. For albumin determinations, a bichromatic bromocresol green dye method was used. Calcium levels were
determined using a cresolphthalein-complexone complex
method, and phosphorous by an ammonium molybdate
bichromatic method (the Amador and Urban [4] modification
of the Daly and Ertingshausen method [ 5 ] ) . Rheumatoid
factor screens were performed using a latex agglutination
tube test kit from Calbiochem-Behring (La Jolla, CA).
Radiographic studies. Roentgenograms were performed on formalin-fixed tissue specimens using a CGR
Medical Corporation (Baltimore, MD) mammography unit.
Roentgenograms of the spine were taken using 27 kV at 5.5
mA seconds with a 0.1-mm focal spot at 1 . 5 magnification.
~
Roentgenograms of the limbs and thoraces were taken at 5
mA seconds. The film screen combination used was Kodak
Ortho M film with a Kodak Min-R screen. Photomacrographs of roentgenograms were taken with a Zeiss dissecting
microscope using indirect transmitted lighting.
Statistical calculations. Data from examination protocols for all anWank mice were tabulated at the conclusion
of the study, after it had been determined clinically which
mice were homozygous ank/ank animals. Data were evaluated in groups according to the age of the mice: 14-20 days
(2 weeks), 21-27 days (3 weeks), etc. The proportion of anW
ank mice detected by examination at each age was calculated
for each parameter in the examination protocol by dividing
the number affected at that age by the total number of anW
ank mice in that group. The mean severity score for all
parameters evaluated at each age was calculated by averaging the scores of all ank/ank mice, whether affected at that
age or not, and the SD and SEM determined for that mean.
The proportion affected and mean severity score were also
determined for males and females separately at each age.
1391
RESULTS
Course of MPA. From the 8 breeder pairs, 51
litters of 334 pups were obtained. Twenty-six died as
neonates. Forty-three of 179 males were affected
(24%) and 24 of 129 females were affected (19%),
substantiating the recessive nature of this trait. Pups
appeared normal at birth. The earliest changes appeared in forepaw digits at 2-3 weeks of age, and
consisted of evanescent swelling with erythema over
proximal interphalangeal (PIP), metacarpophalangeal
(MCP), and wrist joints (Figure 1). Decreased flexion
of the PIP and MCP joints of the forepaws was
detected at 2 4 weeks of age; this progressed in
severity and caused diminished strength of the forepaw grasp (Figure 2). No animal had spontaneous
remission of abnormalities.
Hindpaw abnormalities always developed after
forepaw abnormalities and were detected at 4-7 weeks
of age. Grid cling became impaired as mobility of the
forepaw digits decreased, but animals were able to
Figure 1. Proximal interphalangeal and metatarsophalangeal swelling (arrow) and erythema in the second hindpaw digit of a 4-weekold mouse with acute inflammatory arthritis of murine progressive
ankylosis. Transient erythema and swelling in small joints of the
paws occurred early in the course of the disease. Forepaws were
affected first, at 2-3 weeks of age. Hindpaws were affected at 4-6
weeks of age.
MAHOWALD ET AL
1392
41
FOREFOOTGRASP
2
3
4
5
6
7
8
6
7
8
CLING
4 1
2
3
4
5
WEEKS OF AGE
Figure 2. Progressive loss ofjoint function in the paws of mice with
murine progressive ankylosis. As loss of flexion and ankylosis of the
digits progressed, inability to grasp a wire grid and cling to it when
inverted increased. Numbers within bars are the number of animals
studied at each timepoint. Values are the mean and SEM.
cling to an inverted grid until the hindpaw digits
became inflexible (Figure 2). MCP joints became completely rigid at 4-10 weeks and metatarsophalangeal
(MTP) joints became rigid at 8-12 weeks. Loss of
mobility in the digits produced an abnormal, flatfooted gait. More severe gait abnormalities developed
as wrists and ankles became inflexible, and led to
“rocking” from side to side with each step. Decreased
flexibility was noted in elbows by 7 weeks and in knees
by 14 weeks. Shoulders were affected by 10-12 weeks,
but hips were essentially spared.
Spinal abnormalities were first noted at 6-7
weeks of age, with a change in resting posture, increase in thoracic kyphosis, straightening of the lum-
bar spine, and inability to extend the cervical spine.
With decreased cervical extension, animals were unable to obtain food and water from overhead cage
covers. This necessitated placing food and water on
the cage floor. Spine stiffness progressed between 6
and 12 weeks of age; ultimately, the animals could not
turn and bite (Figure 3). The most sensitive indicator
of decreased spinal mobility was swimming ability.
Slight abnormalities in swimming ability could be
detected at 4-6 weeks of age before changes in posture
were evident. With complete ankylosis of the spine,
animals were unable to swim because of inability to
keep the nose and mouth above water.
Several extraarticular manifestations were
noted. Four female anWank mice developed vaginal
exudates, and most male animals over 10 weeks of age
developed balanitis and priapism (Figure 4), which
were initially attributed to an inability to groom because of spine stiffness. A few animals developed
balanitis at 8-10 weeks of age, however, before spinal
rigidity became marked. During the acute inflammatory phase of the arthritis, some animals developed
fine scaling on dorsal paw surfaces. Later, crusting
and scaling of plantar skin was noted in all anWank
animals after 6 8 weeks of age.
Serum chemistries and serologic results. Blood
chemistry analysis of serum samples from affected
adult anWank animals was performed in the Minneapolis VAMC clinical laboratories. Phosphorus levels
were determined in 3 normal animals and 3 anWank
animals; the mean phosphorus levels were 5.4 and 8.6
mgldl, respectively, both of which are within normal
range. Calcium levels were determined in 2 normal
mice and 2 anWank mice; the means were 8.6 and 9.0
mgldl, respectively, and again, these findings were
within normal range. Albumin levels were determined
in 2 normal mice and 2 anWank mice. The mean for the
normal animals was 2.8 gm/dl (barely within normal
range), and for the anWank animals it was 3.2 (within
normal range). Rheumatoid factor determinations
made in 4 ank/ank adult mice were all negative.
Radiographic changes. Striking radiographic
changes were seen in diarthrodial and axial skeletal
joints. By 4 weeks of age, there was extensive, bilateral, symmetric involvement of all small joints. By 1216 weeks, articular erosions were noted in PIP, MCP,
and MTP joints. Digital joint capsules were calcified,
and frequently, joint spaces contained amorphous
radiopaque material. Carpi and tarsi were enlarged,
and there was extensive wrist and ankle joint destruction along with obliteration of joint spaces. There was
MURINE PROGRESSIVE ANKYLOSIS
1393
HINDTOES PIP
FORETOES PIP
3 8 32 25 31 1 8 25 17
111 2 5 2 4 2 0 14 1 0 6
3
3
L 25
L 25
0
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s
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10 1 1 12 1 3 1 4 15 1 6 1 7 1 8 1 9 2 0 1 1
1 2 1 6 9 lSp13.11
o , ; : ; . : : . . :
0
8 . 4
Figure 3. Distal to proximal progression of ankylosis in mice with murine progressive ankylosis. Loss of range of
motion (ROM) was first seen in the digits of the forepaws and hindpaws, and progressed to involve the wrist, elbow,
and shoulder in the forelimb, and the ankle and knee in the hindlimb. Hips were generally spared. Forelimb
abnormalities were detected 2-3 weeks earlier than hindlimb abnormalities. Numbers below bars are weeks of age;
numbers above bars are the number of animals studied at each timepoint. Values are the means. PIP = proximal
interphalangeal; MCP = metacarpophalangeal; MTP = metatarsophalangeal.
1394
MAHOWALD ET AL
Figure 4. Extraarticular manifestations of murine progressive ankylosis. A, Balanitis with scaling and crusting genital skin lesions developed
in most males. B, Fine scaling of the dorsal and lateral aspect of the paws (arrow) occurred with the evanescent joint swelling and erythema
seen during the acute inflammatory phase of the arthritis. C, Chronic skin changes occurred later, after 2 months of age, on the plantar surfaces
and included scaling and crusting.
enlargement of proximal and distal bone ends with
variable degrees of capsular calcification (Figure 5 ) .
Axial joint abnormalities were evident radiographically at an older age. Syndesmophytes had
developed at costosternal junctions and the junctions
between sternal segments by 3 months of age, producing the appearance of a “bamboo” sternum. Radiographically, sacroiliac joints appeared normal in 4week-old and 8-week-old ank/ank mice. At 12 weeks,
sacroiliac joint margins were slightly indistinct, but no
definite erosions were seen. By 6 months of age,
however, there were large erosions of the sacroiliac
joints of the ank/ank mice, producing “pseudowidening” of the joint space and irregularity of the
inferior joint margins. There was also ankylosis of the
superior joint margins (Figure 6).
At 4 weeks, spines were normal radiographically, but by 8 weeks, erosions at vertebral margins
produced squaring of vertebral bodies. After 12 weeks
of age, extensive marginal syndesmophyte formation
between vertebral bodies with preservation of the disc
space produced a “bamboo” spine. Posterior apophyseal joints were ankylosed. Nonmarginal syndesmophytes were occasionally seen, suggesting calcification
of the paravertebral ligaments (Figure 7).
DISCUSSION
Sweet and Green discounted MPA as a possible
model of AS because they did not find inflammatory
synovitis in mice (1). In our clinical studies of MPA,
we found (as did Hakim et a1 [2]) synovial inflamma-
MURINE PROGRESSIVE ANKYLOSIS
1395
Figure 5. Radiographic views of peripheral forelimb joints (upper panels) and hindlimb joints (lower panels) of 6-month-old
normal mice (a and c) and anWank mice of the same age with murine progressive ankylosis (b and d). Periarticular calcifications
are seen in the digits and wrists, the carpi and distal radius are enlarged, and wrist joint spaces are indistinct because of bony
ankylosis in the ank/ank mouse forelimbs (b). Calcification of joint capsules, irregularity of joint surfaces, cystic changes,
pseudowidening of the metatarsophalangeal joints, and obliteration of the ankle joint space by bony ankylosis are seen in the anW
ank mouse hindlimbs (d). (Original magnification X 7.5.)
1396
MAHOWALD ET AL
Figure 6. Enlarged views of radiographic changes in axial skeletal joints of 6-month-old normal mice (a and c) and anWank mice with murine
progressive ankylosis (b and d). a, Manubriosternum from a normal mouse, showing clear, distinct joint spaces in the costosternal junctions
and manubriosternal joints, with smooth bony margins and no bony bridging (original magnification x 9). b, In the anWank mouse, there are
erosions and bony ankylosis of the manubriosternal joint (white arrow). Costosternal junctions are ankylosed (open arrow) (original
magnification x 9). c, Normal mouse sacroiliac joint, demonstrating smooth sacral and iliac margins on either side of a clearjoint space (original
magnification X 16). d, The sacroiliac joint in the anWank mouse has large erosions, producing irregularity and pseudowidening (closed arrow).
There is ankylosis of the superior portion of the joint (open arrow) (original magnification X 16).
tion in peripheral small joints of 3-4-week-old animals,
before the development of joint ankylosis. The inflammatory synovitis, together with the clinical course,
extraarticular features, and distinctive radiographic
abnormalities, suggest that this disorder does resemble
the human spondylarthropathies (Table 1) (6). The
severity of articular destruction in the peripheral joints
is similar to the arthritis mutilans seen in more severe
cases of psoriatic arthritis or Reiter’s disease (7,8). On
histologic examination, the joint erosions, proliferation of articular and periarticular cartilage and bone,
and tissue calcification observed (1,2) were identical to
those described by Ball (9) and by Calin (10) in AS.
Importantly, the pattern of extensive syndesmophyte
formation and ankylosis seen on roentgenograms is
very similar to that observed in patients with spondylarthropathy .
Hakim and coworkers identified BCP crystals
in the joint fluid from ank/ank mice (2), and therefore
suggested that MPA might be a model of BCP deposition disease. Using x-ray diffraction studies, they
found hydroxyapatite material in the MTP joint fluid of
6-week-old mice. Most samples tested showed only a
weak or very weak relative intensity, suggesting that
there were minute amounts of hydroxyapatite present.
Their method of obtaining SF by “nicking . . . enlarged MCP and MTP joints” and expressing SF
manually could have contaminated the fluid with apatite from calcific deposits in the joint capsules, since
by 6 weeks, MCP and MTP joint capsules of ank/ank
MURINE PROGRESSIVE ANKYLOSIS
1397
Figure 7. Enlarged views of the spine in normal mice (a, c, and e) and in anWank mice (b, d, and f). a, Oblique view, in which the posterior
apophyseal joints are clearly visible (arrow). In an identical view of an anWank spine (b), apophyseal joint spaces are obliterated and ankylosed
(arrow). Nonmarginal syndesmophytes are also visible in this view (arrowhead). Enlarged anteroposterior views of normal (c) and ank/ank (d)
spines demonstrate syndesmophytes produced by ossification of the periphery of the intervertebral discs in the anWank animal (arrow).
Enlarged lateral projections of normal (e) and ankiank (f) spines again demonstrate calcification of the periphery of the intervertebral disc,
producing syndesmophytes in the anWank animal (arrow). (Original magnification x 15.)
MAHOWALD ET AL
1398
Table 1. Comparison of murine progressive ankylosis (MPA) with
human spondylarthropathiesand Milwaukee shoulder syndrome*
Human
spondylarthropathies
Features
Clinical
Inflammatory
peripheral arthritis
Sacroiliitis
Spondylitis
Skin lesions
Genital lesions
Ocular lesions
Pathologic
Pannus
Enthesopathy
Periostitis
Ankylosis
Fibrous
Bony
MPA AS
RD PsA IBD
++ + ++ ++
++ ++ ++ +
++ ++ + +
+ Rare ++ ++
+ o + + +
0
++ ++ Rare
+ + + +
++ ++ ++ +
++ ++ ++ +
+ + + + +
++ ++ + +
++
+
+
Milwaukee
shoulder
2
+
0
0
0
0
0
Rare
f
+
0
+
+
+
+
0
+
0
0
* AS = ankylosing spondylitis; RD = Reiter’s disease; PsA =
psoriatic arthritis; IBD = inflammatory bowel disease-associated
arthritis; ++ = frequent; + = common; f = occasional; rare =
almost never occurs.
mice are calcified. In contrast to human BCP disease,
MPA has extraarticular systemic features. These systemic features and the exuberant new bone formation
are very different from the findings described in the
arthropathy of human BCP crystal deposition disease
(Milwaukee shoulder) ( l l ) , in which there are no
systemic symptoms and the characteristic finding is
extensive bone loss rather than proliferation.
In electron microscopic (EM) studies of MPA,
we found synovial hyperplasia prior to the appearance
of BCP crystals in synovial cells or joint space. In later
stages of ankylosis, intracellular and extracellular BCP
crystals were found in the synovium (12). These EM
studies suggest that BCP crystal deposition follows,
rather than precedes, the initial synovial tissue insult.
It is possible that deposition of these crystals is an
epiphenomenon in MPA, rather than the primary
cause of disease, as suggested by Hakim et al (2).
Intraarticular BCP crystals have been found in
osteoarthritis (OA), rheumatoid arthritis, in normal
human articular cartilage, and in the presence of
calcium pyrophosphate dihydrate crystals (13-15). Apatite has also been demonstrated in fluid from the
subcutaneous tissue of a girl with calcinosis due to
dermatomyositis (13) and in the intervertebral disc
material from a patient with erosive peripheral arthritis, sacroiliitis, and universal spondylodiscitis (16).
Dystrophic calcification is accepted as a consequence
of inflammation and tissue necrosis (17).
There are two schools of thought regarding the
significance of BCP crystals in joint disease. When
Dieppe and colleagues (18) first described BCP crystals in SF from patients with OA, they suggested that
this might be a “third type of crystal-deposition
disease. ” Those investigators also demonstrated that
BCP crystals were inflammatory when injected into rat
pleura or human skin. Similarly, Schumacher et a1 (19)
described BCP crystals in the joint fluid of patients
with a variety of joint diseases, including inflammatory
and erosive OA, and demonstrated that these crystals
were phlogistic when injected into dog knee joints.
Those authors also concluded that “BCP crystals
might be responsible for several clinical syndromes
[including] acute inflammatory arthritis that may
mimic gout [and] may be the cause of some of the
previously unexplained inflammation that is especially
common in ‘erosive arthritis’ or inflammatory osteoarthritis. ”
Later, Dieppe et a1 (20,21) reported finding BCP
crystals in the presence of calcium pyrophosphate
dihydrate crystals in SF from OA patients. There were
no obvious clinical differences between these patients
and other OA patients, and the authors concluded that
“calcification appears to be intrinsic to the evolution
of many cases of osteoarthritis,” but also conceded
that “there is as yet little information on the clinical
and pathological features of osteoarthritis with and
without crystal deposits, and further studies are
needed.” Finally, Dieppe and Doherty (22) concluded,
in a review of the relevant data, that “damaged joint
tissues are especially prone to crystal deposition” and
although “observations help confirm an importaut link
between OA and crystals, they also . . . suggest that a
simple cause and effect relationship is unlikely.” Similarly, Schumacher et a1 (23) concluded, “It seems
unlikely that primary crystal deposition would be
responsible for the onset of OA in all cases. It seems
more likely that a variety of injuries to cartilage
produce an early metabolic-cellular change . . . that
favors crystal deposition.” Hakim and coworkers hypothesized that MPA is caused by the BCP crystals in
the joints, but it is also possible that BCP crystal
deposition follows an as-yet-unidentified articular insult and plays a secondary role in disease pathogenesis
by perpetuating inflammation.
Although MPA is similar to human AS, there
are some important differences. Ocular inflammation
is common in the human spondylarthropathies, but we
MURINE PROGRESSIVE ANKYLOSIS
were unable to find ocular inflammation in MPA,
either by clinical evaluation or histologic study. In the
human spondylarthropathies, both genetic influences
and environmental agents are operative in the pathogenesis of disease. MPA appears to be a purely genetic
autosomal recessive trait. It is possible that some
ubiquitous environmental agent plays a role in the
pathogenesis of MPA in combination with genetic
predisposition. It is also possible that one of the
multiple genes suspected of contributing to susceptibility to disease in the human spondylarthropathies
may be an autosomal recessive gene analogous to the
gene for MPA. The genetics responsible for this group
of diseases have not been defined sufficiently to rule
out that possibility.
In summary, our study of MPA has led us to
conclude that it is a potentially useful model of the
human spondylarthropathies because of extensive AS,
destructive peripheral arthritis, and extraarticular
manifestations. Radiologic findings are similar to, but
more severe than, those usually observed in human
spondylarthropathies. The rapid progression and severity of MPA make it a useful model with which to
study the factors controlling both destructive and
reparative processes in the joints.
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