Osteoclast inhibition impairs chondrosarcoma growth and bone destruction
Department of Cell and Developmental Biology
Animals; Bone Resorption; Bone and Bones; Chondrosarcoma; Diphosphonates; Imidazoles; Male; Osteoclasts; Parathyroid Hormone-Related Protein; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta2
Cell and Developmental Biology | Cell Biology | Neoplasms | Orthopedics
Because Chondrosarcoma is resistant to available chemotherapy and radiation regimens, wide resection is the mainstay in treatment, which frequently results in high morbidity and which may not prevent local recurrence. There is a clear need for improved adjuvant treatment of this malignancy. We have observed the presence of osteoclasts in the microenvironment of chondrosarcoma in human pathological specimens. We utilized the Swarm rat chondrosarcoma (SRC) model to test the hypothesis that osteoclasts affect chondrosarcoma pathogenesis. We implanted SRC tumors in tibia of Sprague-Dawley rats and analyzed bone histologically and radiographically for bone destruction and tumor growth. At three weeks, tumors invaded local bone causing cortical disruption and trabecular resorption. Bone destruction was accompanied by increased osteoclast number and resorbed bone surface. Treatment of rats with the zoledronic acid prevented cortical destruction, inhibited trabecular resorption, and resulted in decreased tumor volume in bone. To confirm that inhibition of osteoclasts per se, and not off-target effects of drug, was responsible for the prevention of tumor growth and bone destruction, we implanted SRC into osteopetrotic rat tibia. SRC-induced bone destruction and tumor growth were impaired in osteopetrotic bone compared with control bone. The results from our animal model demonstrate that osteoclasts contribute to chondrosarcoma-mediated bone destruction and tumor growth and may represent a therapeutic target in particular chondrosarcoma patients.
chondrosarcoma, osteoclast, bisphosphonate, osteolysis
DOI of Published Version
J Orthop Res. 2014 Dec;32(12):1562-71. doi: 10.1002/jor.22714. Epub 2014 Aug 13. Link to article on publisher's site.
Journal of orthopaedic research : official publication of the Orthopaedic Research Society
Otero JE, Stevens JW, Malandra AE, Fredericks DC, Odgren PR, Buckwalter JA, Morcuende J. (2014). Osteoclast inhibition impairs chondrosarcoma growth and bone destruction. Cell and Developmental Biology Publications. https://doi.org/10.1002/jor.22714. Retrieved from https://escholarship.umassmed.edu/cellbiology_pp/143