Enpp1 mutations promote upregulation of hedgehog signaling in heterotopic ossification with aging

Journal of Bone and Mineral Metabolism, 2024 · DOI: https://doi.org/10.1007/s00774-024-01543-1 · Published: August 30, 2024

Genetics Orthopedics

Simple Explanation

This study investigates heterotopic ossification of the tendon and ligament (HOTL), a condition involving abnormal bone formation in tendons and ligaments. The researchers used genetically modified mice to understand how mutations in the Enpp1 gene contribute to HOTL, especially with aging. The study found that mice with Enpp1 deficiency developed progressive heterotopic ossification, particularly in the spine and Achilles tendons, along with knee degeneration. This deficiency also led to increased osteogenic differentiation, suggesting a link between Enpp1 mutations and bone formation. The research indicates that Enpp1 mutations promote ectopic ossification in spinal ligaments and endochondral ossification in tendons by upregulating hedgehog signaling. This provides insights into potential treatment strategies for HOTL by targeting the cellular and molecular mechanisms involved.

Study Duration

28 Weeks

Participants

Male mice (WT, Enpp1flox/flox/EIIa-Cre, Enpp1CKI/+/EIIa-Cre)

Evidence Level

Not specified

Key Findings

1
Enpp1 deficiency leads to progressive heterotopic ossification (HO), especially in the spine and Achilles tendons, and is associated with progressive degeneration of the knees.
2
Fibroblasts from Enpp1flox/flox/EIIa-Cre mice showed greater osteogenic differentiation potential and enhanced hedgehog (Hh) signaling.
3
Mutations in Enpp1 promote ectopic ossification of spinal ligaments and endochondral ossification in tendons and further aggravate knee degeneration by upregulating hedgehog signaling.

Research Summary

The study constructs Enpp1flox/flox/EIIa-Cre mice to model spinal ectopic ossification, providing a basis for future studies on HOTL. These mice exhibit ossified spines and Achilles tendon abnormalities, demonstrating significant hindlimb dysfunction, serving as a model for chronic spinal cord compression. Enpp1 deficiency leads to severe knee degeneration, osteoporosis, and reduced spinal cord function and ankle ROM. This confirms Enpp1 as an anti-aging factor that regulates calcium balance, with mice lacking Enpp1 exhibiting decreased lifespan and early signs of hair whitening. The study found that Enpp1 deficiency-induced ossification in mouse spinal ligaments involves early chondrocyte hypertrophy and late osteogenesis, activating Hh signaling. The expression of Shh, Ptch, and Gli was higher in spinal ligaments of Enpp1flox/flox/EIIa-Cre mice, suggesting that ectopic ossification is an active process.

Practical Implications

Targeted Therapies

Understanding the role of hedgehog signaling in Enpp1-related heterotopic ossification could lead to targeted therapies to inhibit this pathway and prevent or slow down the progression of HOTL.

Early Diagnostics

Identifying Enpp1 mutations as a risk factor for DISH and OPLL can facilitate early diagnosis and intervention strategies to manage bone mineralization and prevent ectopic calcification.

Anti-aging Strategies

Recognizing Enpp1 as an anti-aging factor that regulates calcium balance suggests potential strategies to mitigate age-related bone and joint degeneration by maintaining adequate Enpp1 function.

Study Limitations

1
The study only confirmed the activation of the Hh signal in the spinal HO area and ligament cells of Enpp1 mice without direct evidence that this signal contributes to OPLL progression.
2
The specific mechanism of action of the Hh signaling pathway needs further clarification.
3
The results need further validation in human HOTL samples.

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