Inhibition Of Endochondral Ossification Research Articles

Treating Growth Failure in Achondroplasia

Achondroplasia is an autosomal dominant condition with growth failure due to inhibition of endochondral ossification. In an industry-funded, phase II

Inhibition of Endochondral Ossification during Fracture Repair in Experimental Hypothyroid Rats

Using a rat fracture model, we investigated the effects of a decrease in serum levels of thyroid hormone on the fracture-repair process. Rats were divided into the following groups: (a) controls, (b) those treated with methimazole for the duration of the experiment, and (c) those treated with methimazole and L-thyroxine, receiving both for the same duration. Three weeks after the initiation of pharmacologic treatment, closed femoral fractures were produced. The formation of cartilage tissue in the fracture callus in all rats was not obviously different on day 7 after fracture. In the rats treated with methimazole, differentiation from proliferating to hypertrophic chondrocytes in the fracture callus was less advanced and vascular invasion was clearly inhibited on day 12. Gene expression of alkaline phosphatase and osteocalcin in the callus was significantly lower in these rats than in the controls on days 10, 12, and 14. The mechanical properties of the fracture callus were also significantly weaker in these animals than in the controls on day 21, resulting in impaired fracture repair. These results demonstrate that hypothyroidism inhibits endochondral ossification, resulting in an impaired fracture-repair process. L-thyroxine replacement in the rats treated with methimazole caused the impaired repair process to revert to normal. These results indicate that thyroid hormone is one of the critical systemic factors for fracture repair.

Inhibition of endochondral ossification during fracture repair in experimental hypothyroid rats.

Using a rat fracture model, we investigated the effects of a decrease in serum levels of thyroid hormone on the fracture-repair process. Rats were divided into the following groups: (a) controls, (b) those treated with methimazole for the duration of the experiment, and (c) those treated with methimazole and L-thyroxine, receiving both for the same duration. Three weeks after the initiation of pharmacologic treatment, closed femoral fractures were produced. The formation of cartilage tissue in the fracture callus in all rats was not obviously different on day 7 after fracture. In the rats treated with methimazole, differentiation from proliferating to hypertrophic chondrocytes in the fracture callus was less advanced and vascular invasion was clearly inhibited on day 12. Gene expression of alkaline phosphatase and osteocalcin in the callus was significantly lower in these rats than in the controls on days 10, 12, and 14. The mechanical properties of the fracture callus were also significantly weaker in these animals than in the controls on day 21, resulting in impaired fracture repair. These results demonstrate that hypothyroidism inhibits endochondral ossification, resulting in an impaired fracture-repair process. L-thyroxine replacement in the rats treated with methimazole caused the impaired repair process to revert to normal. These results indicate that thyroid hormone is one of the critical systemic factors for fracture repair.

Physeal distraction and cell proliferation in the growth plate

We studied the cellular response to physeal distraction in the growth plates of skeletally immature rabbits. We used a new method of labelling and detection of proliferating cells with bromodeoxyuridine (BUdR) and an anti-BUdR antibody. The application of an external fixator but no distraction force produced no changes in the growth plates. After five days of distraction at a maximum force of 20 N, the growth plate became thicker, mainly because of an increase in the number of hypertrophic chondrocytes, but there was no evidence of increased cell proliferation. Recent fractures were seen at the junction of growth plate and metaphysis but the increase in bone length was insignificant. After ten days of distraction at the same maximum force, the chondrocyte columns had become disorganised and cell proliferation was significantly decreased. There was an increase in bone length due to distraction of the fracture gap. In this model, physeal distraction did not stimulate cell proliferation, but actually inhibited it. The apparent increase in growth-plate thickness produced by distraction is not due to increased cell production, but results from inhibition of endochondral ossification and the consequent accumulation of hypertrophic chondrocytes. Any growth after distraction depends on the ability of growth-plate chondrocytes to divide. The decrease in proliferative activity which we found after ten days of distraction suggests the need for caution in the use of such procedures in young children.

The effects of maternal hypercortisonism and hypervitaminosis D2 on fetal osteogenesis and ossification in rats.

AbstractPregnant rats were treated daily with intramuscular injections of 5 or 10 mg cortisone acetate dissolved in 0.5 ml normal saline, or orally with 20,000 IU vitamin D2 dissolved in 0.5 ml olive oil, or both. Controls received olive oil and normal saline, or vitamin D2. Treatment was from day 8 or 10 of gestation until the animals were killed on day 18, 20, or 22. The higher dose of cortisone shortened the diaphyses and epiphyses of long bones. Concomitant administration of vitamin D2 caused further bone shortening and hypomineralization. The main microscopic alterations in the fetal bones of cortisone‐treated rats were changes in cartilaginous intercellular substance, narrowing of the hypertrophic and calcifying cartilage cell layer, and inhibition of endochondral ossification. Bone trabeculae were very wide and irregular. The bone matrix had abnormal staining properties. Bone marrow spaces were obliterated and contained a very large number of fibroblasts, preosteoblasts, and osteoclasts. The number of osteoclasts was further increased by treatment with vitamin D2. It is presumed that cortisone passed through the placenta and affected fetal bones, causing the microscopic changes. Concomitant administration of vitamin D2 potentiated the effects of cortisone on bone, and also produced certain specific changes.

Inhibition of Endochondral Ossification in Pantothenic Acid Deficiency

In growing mice, pantothenic acid is essential for the growth of the skeleton. Deficiency of this vitamin causes inhibition of growth and endochondral ossification. The male reacts more quickly to lack of pantothenic acid than the female. On feeding an adequate stock diet subsequent to a prolonged deficiency, growth of cartilage and ossification are resumed rapidly and may surpass in intensity the processes seen in normal nondeficient animals. In the adult mouse, skeletal changes were not observed under the influence of pantothenic acid deficiency.