Induced bone development in transplants of fresh human pseudomalignant heterotopic ossification tissue in athymic...

Biopsy specimens of mature trabecular bone from tumors of two typical cases of pseudomalignant heterotopic ossification (PHO; myositis ossificans circumscripta) were transplanted into athymic nude mice. Specimens of normal metaphyseal bone in adjacent areas were also transplanted in the contralateral hindquarter muscles for controls. By seven days, control bone transplants were necrotic and enveloped in granulation tissues whereas PHO transplants were surrounded by proliferating connective tissue derived from the host-bed muscle tissues. In the intervals from 14 and 21 days, the PHO transplants showed vascular and hypertrophied connective-tissue proliferation with appositional deposits of new bone. The microscopic features of the new bone suggested that it was of mouse host-bed origin because the new bone from Case 1, a female, showed nuclei without sex chromatin. The quantities of new bone were measured by correlated histomorphometric and computer image analysis of microradiographs. Little or no cartilage development was noted at any stage. The normal control trabecular bone tissue was slowly resorbed by macrophages and mononuclear phagocytes; multinucleated giant cells were few and relatively small. Except in one questionably small area of one transplant, nontumorous undemineralized normal human bone failed to induce bone formation within the 28-day period of observation. The quantity of new bone formed in athymic mice in response to implants of PHO, estimated from equivalent quantities of bone developed from implants of lyophilized matrix-free bone morphogenetic protein (BMP) was about 1 microgram/g of wet PHO tumor weight. Although circumstantial evidence implicates BMP in the pathogenesis of heterotopic ossification, more research should be directed toward regional and systemic factors inhibiting bone development in normal and abnormal conditions, including malignant bone tumors.