JPC SYSTEMIC PATHOLOGY
MUSCULOSKELETAL SYSTEM
April 2022
M-M19

 

Signalment (JPC #161962):  A 7-year-old male guinea pig

 

HISTORY:  This guinea pig had a 6-month history of progressive debilitation and inability to use the hind legs.

 

HISTOPATHOLOGIC DESCRIPTION:  Stifle joint, bone and articular cartilage:  Diffusely, the articular cartilage is either completely lost (ulceration) or is thin with decreased matrix basophilia (loss of proteoglycans), multifocal fraying of the surface cartilage (fibrillation), multifocal clefts perpendicular to the joint space that extend into the deep cartilage layers, and occasional clusters of disorganized hyperplastic chondrocytes (chondrones).  In areas of cartilage ulceration, the exposed bone is thickened up to 10x normal (sclerosis).  Subchondral bone multifocally contains multiple cysts, up to 0.5mm in diameter, lined by a single layer of flattened to cuboidal cells.  These cysts occasionally contain eosinophilic fibrillar material and are surrounded by loosely-arranged spindle cells, mild hemorrhage, and hemosiderin-laden macrophages.  Multifocally at the joint margins, there are multiple cartilage-capped, irregularly-shaped proliferations of trabecular woven and lamellar bone (osteophytes) with numerous basophilic resting and reversal lines and a scalloped irregular margin with few osteoclasts present (remodeling), and proliferations of fibrocartilage.  The joint capsule is markedly expanded by mature fibrous connective tissue (fibrosis), and the synovial membrane is mildly thickened multifocally, occasionally forming papillary projections composed of hypertrophied and hyperplastic synoviocytes supported by well-vascularized connective tissue.  Within the joint space, there are low numbers of lymphocytes and necrotic mononuclear cells (synoviocytes or macrophages) mixed with eosinophilic granular to amorphous material.

 

MORPHOLOGIC DIAGNOSIS:  Stifle joint, bone and articular cartilage:  Cartilage degeneration, erosion, and ulceration, diffuse, severe, with fibrillation, clefting, periarticular osteophytes, subchondral bone sclerosis, and subchondral bone cysts (degenerative joint disease), guinea pig (Cavia porcellus), rodent.

 

CONDITION:  Degenerative joint disease (DJD)

 

SYNONYMS:  Osteoarthritis, osteoarthrosis, degenerative arthropathy

 

GENERAL DISCUSSION:

• Degenerative joint disease (DJD) is a common, slowly progressive, often insidious, destructive disease of articular cartilage of synovial joint(s) secondary to various forms of joint injury, characterized by fibrillation, erosion, and ulceration of articular cartilage, subchondral sclerosis, periarticular osteophytes, and osteochondral modeling
  • Three types of joints: Synovial (appendicular skeleton), cartilaginous (intervertebral disks; pubic symphysis), fibrous (sutures in skull; periodontal ligament)
• Microscopic lesions may precede clinical lameness
• Duncan-Hartley guinea pigs housed in laboratories are prone to DJD of the femorotibial joint and are widely used as animal models to study DJD/osteoarthritis; wild guinea pigs do not develop this disease, and the prevalence in the pet population is unknown
  • High levels of ascorbic acid accentuated the diseases in laboratory housed Duncan Hartley guinea pigs via activation of TGF-beta
• Primary DJD: Cause is inapparent; seen in older animals
• Secondary DJD: Disease due to known predisposing cause resulting in direct damage to articular cartilage, creates instability, or results in abnormal directional forces, e.g. traumatic, nutritional, conformational, or developmental (e.g. hip dysplasia, osteochondrosis, angular limb deformities); these lesions are often more severe than those of primary DJD at post-mortem examination

 

PATHOGENESIS:

• Etiopathogenesis of DJD is incompletely understood, and likely the result of multiple diseases with similar endpoints involving interaction between biologic and mechanical factors on the articular cartilage, subchondral bone, and synovium; primarily degenerative with secondary inflammation; evidence that chondrocytes play an important role as do various cytokines and growth factors
• Initial loss of proteoglycan aggregates of aggrecan (major constituent of cartilage matrix) in articular cartilage mediated by degradative enzymes (proteoglycanases, metalloproteinases, serine proteinases, cysteine proteinases, aggrecanase), and increased water content (not bound as it normally is to proteoglycans) à exposure of collagen fibrils (fibrillation), swelling, chondromalacia, ultrastructural loss of layer covering articular cartilage à loss of lubrication, continued proteoglycan loss à progressive erosion, collagen fiber collapse perpendicular to the joint surface, cartilage breakdown à release of inflammatory mediators (IL-1, IL-6, TNF-α, +/- neuropeptide substance P) à inflammation (e.g. mild synovitis), increased synthesis of degradative enzymes
  • Many degradative enzymes are derived from chondrocytes; normal articular cartilage contains inhibitors of these enzymes but not in DJD; the most important degradative enzymes are the collagenases, stromelysins, and gelatinases; plasmin and tissue plasminogen activator also activate these enzymes
    • Collagenase breaks down type II collagen
    • Stromelysin cleaves aggrecan and some types of collagen
• Articular capsule fibrosis, osteophytosis, joint incongruity à decreased range of motion
• Joint instability -> marginal (periarticular) osteophyte formation and remodeling of the metaphyseal and epiphyseal bone, +/- eventual joint ankylosis

                                                                   

TYPICAL CLINICAL FINDINGS:

• Can affect any age animal, can be clinically apparent or silent, can affect one or multiple joints (monoarticular or polyarticular)
• Pain, deformity, and decreased mobility; the advanced stage is the most painful
• Laboratory-housed Duncan-Hartley guinea pigs: spontaneously develop DJD in the stifle joints, lesions are apparent by 3 months of age and progress with age

 

TYPICAL GROSS FINDINGS:

• Variable joint enlargement, deformity, variable lesion distribution within the joint
• Early: The earliest gross lesion is roughening (“fibrillation”) of the articular cartilage on weight-bearing surfaces; mild chondromalacia (yellow-brown, with fibrillation and roughened, opaque articular surface)
• Mild: Normal, or superficial cartilage erosions +/- reduced cartilage thickness
• Moderate: Focally extensive areas of fibrillation of articular cartilage
• Chronic: Full-thickness loss of articular cartilage with subchondral bone exposure (cartilage ulceration), subchondral bone thickening/sclerosis, smooth polished appearance of subchondral bone surface (eburnation), +/- marginal (periarticular) osteophytes, joint capsule thickening, +/- subchondral bone cysts
  • Eburnation: to become ivory-like
  • Osteophytes: small nodular outgrowths of bone covered by a thin layer of hyaline cartilage that form at the margin of articular cartilage and bone, can be detected as early as 7 days following experimental destabilization of joints
• Articular cartilage of hinge-type joints (e.g. hock, fetlock, elbow) often has linear grooves (“wear lines”) in the direction of joint movement, especially in adult horses

 

TYPICAL LIGHT MICROSCOPIC FINDINGS:

• Early: Decreased metachromatic staining of superficial cartilage matrix (probably due to proteoglycan loss); some investigators think mild subchondral bone thickening (sclerosis) may precede cartilage lesions
• Mild: Superficial cartilage degeneration including chondrocyte degeneration/death (associated with linear depressions) and superficial fibrillation (unmasking of superficial collagen fibrils); +/- clusters of proliferative chondrocytes (chondrones, or isogenous groups) especially adjacent to cartilage fissures, and decreased density of chondrocytes in other areas
• Moderate: Articular cartilage loss of integrity with fibrillation and tissue loss extending into middle and deep zones, +/- mild synovitis, +/- focally extensive subchondral bone thickening (sclerosis), +/- periarticular osteophytes
• Chronic: Marked reduction in articular cartilage thickness with deep clefts, an irregular surface, and prominent collagen fibrils in cartilage matrix blend into areas of full thickness (ulceration); severely thickened subchondral bone (sclerosis), periarticular osteophytes often present, +/- subchondral cysts, chronic mild to moderate lymphoplasmacytic synovitis with fibrosis +/- synovial villous hypertrophy with occasional branching, fibrosis of the articular capsule
  • Synovium: magnitude of synovial inflammation is much less than with inflammatory arthridities, and synovial fluid is clear and colorless without inflammatory exudates but may have reduced viscosity; fragments of cartilage probably from the articular surface may be attached or embedded
  • Subchondral bone cysts: more common in humans than domestic animals; synovial-like lining with peripheral osteoclastic bone lysis and fibrosis, presumably form secondary to fissures in overlying cartilage or eburnated bone allowing synovial fluid to be forced into subchondral bone; Hartley guinea pigs develop these cysts in the proximal tibial articular surface that form from invaginations of synovial membranes surrounding cruciate ligaments as they insert into the subchondral bone

 

ADDITIONAL DIAGNOSTICS:

• Radiographs: the most common clinical technique used to routinely confirm osteoarthritis/DJD; features of DJD include narrowing of the joint space, subchondral bone sclerosis, remodeling, subchondral bone cysts, and marginal osteophytes

 

DIFFERENTIAL DIAGNOSIS:

• Infectious arthritis: Streptococcus spp, E. coli, Mycoplasma spp; usually arthritis is secondary to a systemic infection, so there may be other lesions; will generally see inflammatory cells (especially neutrophils); +/- fibrin in the synovial fluid
• Immune mediated arthritis: Usually a response to persistent antigenic material within the joint or deposition of immune complexes; can be difficult to distinguish from infectious arthritis because neutrophils are often present in the synovial fluid

 

COMPARATIVE PATHOLOGY:

• Humans: osteoarthritis is one of the most important chronic health issues but pathogenesis is poorly undestood; multiple animal models have been developed to study the disease including mouse, rat, guinea pig, sheep, goat, and horse
• Horses: Common cause of economic loss; commonly affects the interphalangeal, metacarpophalangeal, and tarsal joints which are subjected to high biomechanical loading during motion especially in performance horses
  • Interphalangeal joints (“ringbone”): predominantly affects the forelimb, although disease secondary to fractures or osteochondrosis most commonly affects the hindlimbs
  • Metacarpophalangeal joints (fetlock), traumatic and degenerative disease is more common in the metacarpophalangeal (fetlock) joint than any other limb joint with traumatic synovitis related to pressure on the joint capsule and with progressive changes as described above resulting in synovitis and thickening of the joint capsule; other changes such as formation of a periarticular lip on the proximal phalanx, subchondral bone lysis on the condyle of the cannon bone and cartilage erosion and ulceration on the transverse ridge of the condyle of the cannon bone (transverse ridge arthrosis) are also described
  • Hock joints: Most commonly affects the medial side of the tarsus, and most commonly involves the distal intertarsal joint; early DJD lesions involving soft tissues only is called “bog spavin”, “blind spavin”, or “jack spavin”, while later DJD bony lesions are called “bone spavin”)
  • Navicular bone (distal sesamoid bone): DJD of the navicular bone, adjacent deep digital flexor tendon, and intervening navicular bursa ("navicular syndrome/disease") is common, especially in the forelimbs, and is often bilateral
  • Carpometacarpal joint: DJD occurs secondary to repetitive trauma in racehorses, or occurs “spontaneously” in older non-racing Quarter Horses and Arabian horses (Engiles, Jour Vet Diagn Invest. 2017)
  • Temporohyoid joint: Bilateral proliferative changes with club-shaped proximal stylohyoid bone, rounding of the synostosis of the petrous temporal bone, and extension of osteophytes from the petrous temporal bone that often envelope the stylohyoid head and may bridge the joint; clinically manifests as head shaking, ear rubbing, dysphagia; fracture of ankylosed joint may cause facial paralysis and/or acute vestibular signs; older horses most commonly affected
• Cattle (especially bulls): DJD often affects the stifle, hip, and tarsal joints, usually secondary to trauma or inflammation; stifle DJD especially affects mature dairy cows and stud dairy and beef bulls, possibly inherited in Holstein and Jersey breeds, lesions especially on the medial aspect of the distal femur and proximal tibia
• Dogs: DJD is relatively common, often in weight-bearing joints in medium and large breed dogs (especially shoulder, hip, stifle); hip dysplasia and obesity are predisposing conditions (hip dysplasia is heritable); DJD also affects stifle and scapulohumeral joints
  • Primary DJD is sufficiently common to be nearly inevitable with aging; gross lesions are common at necropsy even without history of lameness
  • Shoulder DJD may be difficult to differentiate from osteochondrosis; both occur at the caudal aspect of the humeral head, both are bilateral, but DJD occurs later in life often secondary to joint instability and osteochondrosis occurs earlier in life
  • A recent study identified degenerative disease of the temporomandibular joint in domestic dogs, including perforation of the fibrous discs (Lin, J Comp Pathol. 2018)
• Cats: DJD is much less common than in dogs; most commonly affects shoulder, elbows, hips, tarsal joints; Siamese cats with unexpectedly severe DJD should be screened for mucopolysaccharidosis VI (D520N mutation causes mild mucopolysaccharidosis disease but leads to high incidence of DJD); DJD may predispose to synovial cyst formation with potential to transform into synovial myxoma (Craig,Vet Pathol. 2020)
• Mice: DJD arises in aged mice especially in stifle joints; obesity increases the severity of DJD
• Rats: DJD occurs in sites including the sternum and femur in aged rats
• Hamsters: Syrian hamsters predisposed
• Wildlife:
  • Common in aged and captive bovids, cervids, giraffes, okapi, hippopotamuses, African and Asian elephants, ursids, mustelids, rhinoceroses, bats, waterfowl; often major factor in decision to euthanize geriatric animals
  • Cervids: May be secondary to trauma or infection; associated with poor nutrition early in life in moose; increased risk of predation; coxofemoral joint is most commonly affected joint in moose vs. stifle in white-tailed deer
  • Elephants: Forelimbs are more commonly and severely affected due to greater weight bearing stress
  • Grey wolves: Recent study found 11.6% of reviewed specimens to have temporomandibular joint osteoarthritis (Döring, J Comp Pathol. 2019)
  • Kit foxes: Recent study found 5.9% of reviewed specimens had low grade temporomandibular joint osteoarthritis (Yanagisawa, J Comp Pathol. 2019)
• Nonhuman primates: Osteoarthritis affects many Old World monkeys and apes but is uncommon in free-ranging New World primates; the knee joint is most commonly affected; there is a similar spectrum of arthritic diseases as humans; disease is polygenetic, more common in females than males, and may be associated with obesity
  • Baboons: Spontaneous temporomandibular joint arthropathy
  • Rhesus and cynomolgus macaques: Age-associated spontaneous DJD is an excellent model for human osteoarthritis; the stifle is the most commonly affected synovial joint in rhesus macaques (vertebral osteoarthritis, affecting cartilaginous joints, is extremely common also)
• Intervertebral disk disease (affects cartilaginous joints, see N-M27): Age-related disease in many species, most significant in humans and dogs, resulting from a change in composition of the nucleus pulposis of the intervertebral disk à degeneration of the annulus fibrosus à tears or fissures in the annulus à herniation or bulging of nucleus pulposus material; dorsal herniation of disk material into the spinal canal is the most common cause of paresis and paralysis in dogs
  • Hansen Type I (most common in chondrodystrophic breeds, e.g. dachshund, pekingese, poodle, beagle, cocker spaniel with expressed fibroblast growth factor 4 retrogene): chondroid metaplasia of the nucleus pulposus of all disks followed by calcification in the first year of life à disk prolapse, rupture, often acute extrusion of disk material into the vertebral canal à spinal cord compression
  • Hansen Type II (Nonchondrodystrophic dogs, pigs, cats, rarely horses; “senile degenerative disk disease”): Progressive dehydration and collagenization of normal nucleus pulposus, calcification is rare; disk prolapse secondary to partial rupture of the annulus fibrosis with bulging into the vertebral canal; may lead to DJD of articular facets à impingement on spinal nerves and/or compression of spinal canal and/or spondylosis that may result in ankylosis; generally only a single disk involved (unlike type I IVDD)

 

REFERENCES:

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2. Craig LE, Dittmer KE, Thompson KG. Bones and joints. In: Maxie MG, ed. Jubb, Kennedy, and Palmer’s Pathology of Domestic Animals. Vol 3. 6th ed. St. Louis: Elsevier; 2016:137-146.
3. Craig LE, Krimer PM, O'Toole AD. Synovial Cysts and Myxomas in 16 Cats. Vet Pathol. 2020;57(4):554-558.
4. Delaney MA, Treuting PM, Rothenburger JL. Rodentia. In: Terio K, McAloose D, Leger J, eds. Pathology of Wildlife and Zoo Animals, San Diego, CA: Elsevier 2018: 499.
5. Döring S, Arzi B, Winer JN, Kass PH, Verstraete FJM. Dental and Temporomandibular Joint Pathology of the Grey Wolf (Canis lupus). J Comp Pathol. 2018;160:56-70.
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23. Yanagisawa N, Wilson RE, Kass PH, Verstraete FJM. Dental and Temporomandibular Joint Pathology of the Kit Fox (Vulpes macrotis). J Comp Pathol. 2019;167:60-72.

 

 

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