Prevention of Bone Growth Defects, Increased Bone Resorption and Marrow Adiposity with Folinic Acid in Rats Receiving Long-Term Methotrexate

Chia-Ming Fan,Susanta K Hui,Cory J Xian,Bruce K Foster,Dominique Heymann

doi:10.1371/journal.pone.0046915

Chia-Ming Fan, Susanta K Hui + Show 3 more

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https://doi.org/10.1371/journal.pone.0046915

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Abstract

The underlying pathophysiology for bone growth defects in paediatric cancer patients receiving high dose methotrexate chemotherapy remains unclear and currently there are no standardized preventative treatments for patients and survivors. Using a model in young rats, we investigated damaging effects of long-term treatment with methotrexate on growth plate and metaphyseal bone, and the potential protective effects of antidote folinic acid. This study demonstrated that chronic folinic acid supplementation can prevent methotrexate-induced chondrocyte apoptosis and preserve chondrocyte columnar arrangement and number in the growth plate. In the metaphysis, folinic acid supplementation can preserve primary spongiosa heights and secondary spongiosa trabecular volume by preventing osteoblasts from undergoing apoptosis and suppressing methotrexate-induced marrow adiposity and osteoclast formation. Systemically, plasma of folinic acid supplemented rats, in comparison to plasma from rats treated with MTX alone, contained a significantly lower level of IL-1β and suppressed osteoclast formation in vitro in normal bone marrow cells. The importance of IL-1β in supporting plasma-induced osteoclast formation was confirmed as the presence of an anti-IL-1β neutralizing antibody attenuated the ability of the plasma (from MTX-treated rats) in inducing osteoclast formation. Findings from this study suggest that folinic acid supplementation during chronic methotrexate treatment can alleviate growth plate and metaphyseal damages and therefore may be potentially useful in paediatric patients who are at risk of skeletal growth suppression due to chronic methotrexate chemotherapy.

Highlights

Bone growth involves the production of calcified cartilage in the growth plate, which will be first converted into woven spongy bone and further modeled and remodeled into lamellar trabecular bone in the metaphysis [1]
Since bone growth defects or bone loss during childhood may predispose to osteopenia and osteoporosis in later life, it is important to understand the mechanisms of chemotherapyinduced bone damage to the growing bones and develop strategies for prevention of such damages
Counting of cells per chondrocyte column revealed a significant reduction of chondrocyte numbers after long-term MTX treatment compared to control rats (P,0.01), while supplementary treatment with Folinic acid (FA) partially preserved the chondrocyte numbers (P,0.05 vs. MTX) (Fig. 2H)

Summary

Introduction

Bone growth involves the production of calcified cartilage in the growth plate, which will be first converted into woven spongy bone (composed of bony trabeculae of mineralized cartilage cores in the primary spongiosa region) and further modeled and remodeled into lamellar trabecular bone (secondary spongiosa) in the metaphysis [1]. These processes rely on the regulation of growth plate chondrocyte proliferation, differentiation and apoptosis, and differentiation and function of bone-forming cells (osteoblasts) and bone resorptive cells (osteoclasts). Since bone growth defects or bone loss during childhood may predispose to osteopenia and osteoporosis in later life, it is important to understand the mechanisms of chemotherapyinduced bone damage to the growing bones and develop strategies for prevention of such damages

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