Molecular structure and function of microfibrillar-associated proteins in skeletal and metabolic disorders and
Sipin Zhu1,2, Lin Ye3, Samuel Bennett2
1Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, China.
Abstract:
Microfibrillar-associated proteins (MFAPs) are extracellular matrix glycoproteins, which play a role in microfibril assembly, elastinogenesis, and tissue homeostasis. MFAPs consist of five subfamily members, including MFAP1, MFAP2, MFAP3, MFAP4, and MFAP5. Among these, MFAP2 and MFAP5 are most closely related, and exhibit very limited amino acid sequence homology with MFAP1, MFAP3, and MFAP4. Gene expression profiling analysis reveals that MFAP2, MFAP5, and MFAP4 are specifically expressed in osteoblastic like cells, whereas MFAP1 and MFAP3 are more ubiquitously expressed, indicative of their diverse role in the tropism of tissues. Molecular structural analysis shows that each MFAP family member has distinct features, and functional evidence reveals discrete purposes of individual MFAPs. Animal studies indicate that MFAP2-deficient mice exhibit progressive osteopenia with elevated receptor activator of NF-κB ligand (RANKL) expression, whereas MFAP5-deficient mice are neutropenic, and MFAP4-deficient mice displayed emphysema-like pathology and the impaired formation of neointimal hyperplasia. Emerging data also suggest that MFAPs are involved in cancer progression and fat metabolism. Further understanding of tissue-specific pathophysiology of MFAPs might offer potential novel therapeutic targets for related diseases, such as skeletal and metabolic disorders, and cancers.
Insights
Microfibrillar-associated proteins (MFAPs) are key extracellular proteins. MFAP research reveals distinct roles in bone health, immune function, and lung disease, offering potential therapeutic targets.
Area of Science:
- Biochemistry
- Molecular Biology
- Extracellular Matrix Biology
Background:
- Microfibrillar-associated proteins (MFAPs) are glycoproteins in the extracellular matrix.
- They are crucial for microfibril assembly, elastinogenesis, and maintaining tissue homeostasis.
- The MFAP family comprises five members (MFAP1-5) with varying structural and functional characteristics.
Purpose of the Study:
- To explore the distinct roles and tissue-specific functions of MFAP family members.
- To investigate the implications of MFAP deficiencies in various physiological and pathological conditions.
- To identify MFAPs as potential therapeutic targets for skeletal, metabolic, and oncological diseases.
Main Methods:
- Gene expression profiling to determine tissue-specific expression patterns.
- Molecular structural analysis to understand distinct protein features.
- Phenotypic analysis of genetically modified animal models (MFAP-deficient mice).
Main Results:
- MFAP2 and MFAP5 show close homology, distinct from MFAP1, MFAP3, and MFAP4.
- MFAP2, MFAP4, and MFAP5 are osteoblast-associated; MFAP1 and MFAP3 are ubiquitously expressed.
- MFAP2 deficiency leads to osteopenia; MFAP5 deficiency causes neutropenia; MFAP4 deficiency results in emphysema-like pathology and impaired neointimal hyperplasia.
- Emerging evidence links MFAPs to cancer progression and fat metabolism.
Conclusions:
- Individual MFAPs possess unique structures and functions, contributing to diverse physiological processes.
- MFAP deficiencies result in specific pathologies, highlighting their critical roles in tissue homeostasis.
- Targeting MFAPs may offer novel therapeutic strategies for skeletal disorders, metabolic diseases, and cancers.
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