23-month-old female Corriedale sheep (Ovis aries).The sheep was in good condition, but had been showing increasing reluctance to rise over the previous weeks. The front limbs were extremely bowed, and there was pronounced thoracic lordosis. This sheep was part of an embryo transfer trial using semen and ovum from sheep affected with suspected inherited rickets. The sheep were on good quality pasture with high soil phosphorus levels.
On post-mortem examination there was segmental thickening of the distal radial physis, and enlargement of the costochondral junctions of ribs 5-10. The radius showed dorsal and valgus curvature. All the long bones had thickened cortices, and enthesiophytes were present around the carpal and tarsal joints.
The physeal lesion is characterized by irregular segmental thickening of the hypertrophic zone and disorganization of chondrocyte columns. Tongues and islands of persistent hypertrophic chondrocytes extend from the physis into the metaphysis. The cartilage matrix in some areas is eosinophilic an interspersed with fibrin. The metaphysis consists of thickened, disorganized trabeculae of woven bone, fibrous connective tissue, degenerate cartilage matrix, fibrin and hemorrhage merging into thick trabeculae of lamellar bone. In some sections osteoclastic resorption cavities are present in the cortex, and occasionally within trabeculae. Wide osteoid seams line some trabeculae.
Rib: Osteodystrophy with physeal thicke-ning and unmineralized osteoid seams.
Calcium 1.97 mmol/L (2.0-2.7)
Phosphate: 0.73 mmol/L (1.3-2.7)
25-hydroxyvitamin D3: 36 nmol/L (no difference compared with control sheep)
1,25-dihydroxyvitamin D3: 154 pmol/L (no difference compared with control sheep)
Rickets is a metabolic bone disease, most commonly due to either phosphorus deficiency or vitamin D deficiency. The classical lesions of rickets include: Segmental thickening of growth plates (particularly of rapidly growing bones), enlargement of costochondral junctions (the so-called rachitic rosary), and spontaneous fractures.(10) In cattle, pigs and sheep collapse of subchondral bone of the humeral head is also described. Impaired mineralization of the physis and newly formed osteoid leads to islands and tongues of hypertrophic chondrocytes extending into the metaphysis, disorganization of the primary spongiosa, thick osteoid seams lining trabeculae and micro fractures.(10) Rarely, rickets may be due to inherited defects in vitamin D metabolism or renal tubular function. See the recent review on vitamin D metabolism and rickets for further details.(4)
In Corriedale sheep with autosomal recessive inherited rickets,(3,5) a novel nonsense mutation in the noncollagenous bone protein, dentin matrix protein 1 (DMP1), leading to a premature stop codon and truncation of the protein has been found (personal communication, K. Dittmer). The equivalent form of this disease in humans is called autosomal recessive hypophosphataemic rickets I. The mutation in DMP1 leads to increased serum fibroblast growth factor 23 (FGF23) concentration. FGF23 inhibits the renal NPT-2a cotransporter (a Na-P cotransporter) and CYP27B1 (1α-hydroxylase) activity in the kidney, altering phosphate reabsorption in the renal tubules, and inhibiting 1,25(OH)2D3 production. Consequently, humans with this condition have hypophosphataemia, phosphaturia, inappropriately normal serum 1,25(OH)2D3 concentrations and rickets.(6)
The thickened cortices seen in the long bones of affected sheep(2) and enthesiophytes are a feature of X-linked hypophosphataemic rickets in humans.(9) The pathogenesis of this is unclear. However in the sheep, we hypothesize that the enthesiophytes are the result of strain on ligament/tendon attachments to weakened, poorly mineralised bone. Likewise, the thickened cortices are a consequence of bone being deposited at sites of strain in order to decrease deformation associated with mechanical loading, as described by Wolffs law or the mechanostat model.(7,8)
This inherited disease has the potential to be widespread in Corriedale sheep worldwide. A test for heterozygous animals has been developed.
Rib bone: Physeal chondrodysplasia, diffuse with excessive proliferation of the zone of hypertrophy, retained cartilage cores, lack of mineral-ization and myelofibrosis.
The histologic description given in conference was very similar to the contributors description. The absence of mineralized cartilage and decreased number of normal osteoclasts, along with the abnormal distribution of chondrocytes into disorganized clusters (rather than forming organized columns or rows) with scattered chondrocyte necrosis were also described and discussed. Some conference participants noted the presence of enthesiophytes at sites of tendon/ligament attachment, although this was not a feature present in all slides. This observation led to
specific discussion of how enthesiophyte formation relates to the pathogenesis of inherited rickets, as addressed in the contributors comment above.
The lesions of rickets result from failure of mineralization, which includes both impaired endochondral ossification and failed mineralization of osteoid. This results in the presence of excess osteoid as well as the prominent nodular thickenings of cartilage which are apparent grossly. The enlarged irregular physis is composed of increased numbers of disorganized chondrocytes, as seen in this case. The metaphyses are flared secondary to impaired osteoclast removal of cartilage and unmineralized bone (osteoid) from the cutback zones. Osteoclasts cannot bind unmineralized matrix, impairing remodeling and resulting in accumulation of unmineralized osteoid and cartilage.(1) Naturally occurring rickets is uncommon in sheep, cattle, horses, dogs, and cats; llamas and alpacas are highly susceptible and pigs are susceptible when they dont receive adequate feed supplementation. There is also a genetic form in pigs which is similar to a condition that occurs in people.(4) Like rickets, the pathogenesis of osteomalacia also involves defective mineralization, but is a condition that occurs in adult animals after the growth plates have closed and therefore does not involve growth plates. Osteo-malacia results in increased amounts of unmineralized osteoid at sites of pressure or stress.
Vitamin D3 is formed in the skin and can also be absorbed in the diet, as can vitamin D2. It is stored in fat or transported to the liver where it must undergo the first step of activation, hydroxylation. Once hydroxyl-lated in the liver, 25-hydroxycholecalciferol [25(OH)D3], which is the primary form of vitamin D in circulation, must again be hydroxylated in the kidney by 1α-hydroxylase, to form1, 25-dihydrox-ycholecalciferol [1,25(OH)2D3], the metabolically active form of vitamin D. Formation of this metabolically active form in the kidney is regulated by serum phosphorus and calcium concentrations and parathyroid hormone. The metabolically active form of vitamin D acts to mobilize calcium from bone in order to maintain serum calcium concentration, by maturation and activation of osteoclasts. The precise mechanism by which vitamin D influences bone growth is not completely understood, but may be indirectly through calcium and phosphorus concentration, or through direct interaction with osteoblasts and chondrocytes.(4)
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