Involvement of the Toll-like receptor 4 pathway and use of TNF-α antagonists for treatment of the mucopolysaccharidoses

Abstract

Enzyme replacement therapy is currently available for three of the mucopolysaccharidoses (MPSs) but has limited effects on the skeletal lesions. We investigated the involvement of the Toll-like receptor 4 (TLR4) signaling pathway in the pathogenesis of MPS bone and joint disease, and the use of the anti-TNF-α drug, Remicade (Centocor, Inc.), for treatment. TLR4 KO (TLR4 (lps−/−) ) mice were interbred with MPS VII mice to produce double-KO (DKO) animals. The DKO mice had longer and thinner faces and longer femora as revealed by micro-computed tomography analysis compared with MPS VII mice. Histological analyses also revealed more organized and thinner growth plates. The serum levels of TNF-α were normalized in the DKO animals, and the levels of phosphorylated STAT1 and STAT3 in articular chondrocytes were corrected. These findings led us to evaluate the effects of Remicade in MPS VI rats. When initiated at 1 month of age, i.v. treatment prevented the elevation of TNF-α, receptor activator of NF-κB, and other inflammatory molecules not only in the blood but in articular chondrocytes and fibroblast-like synoviocytes (FLSs). Treatment of 6-monthold animals also reduced the levels of these molecules to normal. The number of apoptotic articular chondrocytes in MPS VI rats was similarly reduced, with less infiltration of synovial tissue into the underlying bone. These studies revealed the important role of TLR4 signaling in MPS bone and joint disease and suggest that targeting TNF-α may have positive therapeutic effects.bone and joint disease | inflammation | glycosaminoglycans | growth plate

Growth Charts for Individuals with Mucopolysaccharidosis VI (Maroteaux–Lamy Syndrome)

“…Growth plate abnormalities and disorganization secondary to GAG accumulation most likely contribute to growth failure in MPS disorders. Disruption of chondrocyte proliferative and hypertrophic zones in the growth plate secondary to GAG accumulation, cytokine/inflammatory response, and cellular dysfunction may lead to early bone maturation and impaired growth velocity (Abreu et al 1995;Alliston 2010;Simonaro et al 2010). …”

Establishment of glycosaminoglycan assays for mucopolysaccharidoses

“…Accumulation of GAGs can induce pro-inflammatory factors such as IL-1β, 6, and 10 and TNF-α [14]. Accumulated GAGs and/or pro-inflammatory factors promote the synthesis of KS secondarily.…”

“…Enzyme replacement therapy (ERT) [3][4][5], hematopoietic stem cell transplantation (HSCT) [6][7][8][9], substrate reduction therapy (SRT) [10,11], gene therapy [12,13], and anti-inflammatory drugs [14,15] are in clinical use or being investigated under clinical trials for patients with some types of MPS. Initiating these treatments at birth or during early stages provides most benefits in the clinical improvement of the disease.…”

Therapies for the bone in mucopolysaccharidoses

“…The effect of anti-inflammatory drugs was assessed in MPS VI rats. Early treatment in the presymptomatic period inhibited the elevation of TNF-α, RANKL and other inflammatory factors in the blood, articular chondrocytes and synovial fibroblasts [36]. However, there was no impact on bone growth or mobility since stored GAGs still remained in chondrocytes of the growth plate.…”