MPSI Manifestations and Treatment Outcome: Skeletal Focus

Abstract

Mucopolysaccharidosis type I (MPSI) (OMIM #252800) is an autosomal recessive disorder caused by pathogenic variants in the IDUA gene encoding for the lysosomal alpha-L-iduronidase enzyme. The deficiency of this enzyme causes systemic accumulation of glycosaminoglycans (GAGs). Although disease manifestations are typically not apparent at birth, they can present early in life, are progressive, and include a wide spectrum of phenotypic findings. Among these, the storage of GAGs within the lysosomes disrupts cell function and metabolism in the cartilage, thus impairing normal bone development and ossification. Skeletal manifestations of MPSI are often refractory to treatment and severely affect patients' quality of life. This review discusses the pathological and molecular processes leading to impaired endochondral ossification in MPSI patients and the limitations of current therapeutic approaches. Understanding the underlying mechanisms responsible for the skeletal phenotype in MPSI patients is crucial, as it could lead to the development of new therapeutic strategies targeting the skeletal abnormalities of MPSI in the early stages of the disease.

Keywords: endochondral bone formation; glycosaminoglycans; lysosomal alpha-L-iduronidase; lysosomal storage disease; mucopolysaccharidoses; mucopolysaccharidosis type I.

Figure 1

Disease manifestation onset in severe MPSI patients. Timeline of clinical manifestations in severe MPSI with focus on skeletal findings. Created with BioRender.com (accessed on 16 September 2022).

Figure 2

Schematic representation of a proteoglycan (top) and structure of principal GAG chains (bottom).

Figure 3

Representative pathological MPSI cascade. GAG accumulation inside the lysosome could be responsible for lysosome rupture with subsequent release of proteases, cathepsins, and toxic products inside the cytoplasm. This could potentially result in mitochondrial oxidative stress, ROS formation, impaired cell function, and eventually, apoptosis. Created with BioRender.com (accessed on 16 September 2022).

Figure 4

Main transcription factors and signaling pathways in endochondral bone formation. The left panel shows an undecalcified von Kossa/methylene blue-stained section of the femur of 1-day-old mouse showing mineralized matrix (black color) in the hypertrophic zone and in the underlying trabecular bone. The right panel illustrates the main matrix proteins and molecules secreted by chondrocytes and their transcription factors’ expression during the different differentiation stages. Resting and proliferating chondrocytes express SOX9 and produce collagen type II and aggrecan, respectively; pre-hypertrophic and hypertrophic chondrocytes express IHH, which induces the expression of PTHrP close to the articular region. PTHrP, in turn, blocks the expression of IHH in lower chondrocytes and regulates chondrocyte proliferation and hypertrophy. In addition, PTHrP maintains chondrocytes in their proliferative phase, promoting the activity of SOX9 and the inhibition of RUNX2, which is expressed by pre- and hypertrophic chondrocytes, and it is important for the production of collagen type X and MMP13 and the induction of osteoblastogenesis.