
-   Elderly mice were shown to exhibit significant age-induced skeletal pathology, which correlated with a significant increase in skeletal stem/progenitor cells (SSPCs) in bone marrow (BM). Alpha-2-macroglobulin (A2M) as one of the most downregulated transcripts in SSPCs isolated from the BM of elderly vs. mature mice, and silencing of A2M expression in human BM-MSCs induced their proliferation and skewed their lineage bifurcation toward adipogenesis at the expense of osteogenesis thereby recapitulating critical aspects of age-induced stem cell dysfunction [PMID: 37965574]. Adrenocorticotropic hormone (ACTH), as an osteoblastic differentiation enhancer, up-regulates A2M gene expression in osteoblasts derived from human mesenchymal stem cells (MSCs), which promotes osteoblastic differentiation probably through TGF-beta induction [PMID: 32163666].
-   Oxidization of alpha2M by hypochlorite leads to its increased binding to TNF-alpha, IL-2, and IL-6 and decreased binding to beta-NGF, PDGF-BB, TGF-beta1, and TGF-beta2. Oxidation serves as a switch mechanism that down-regulates the progression of acute inflammation by sequestering TNF-alpha, IL-2, and IL-6, while up-regulating the development of tissue repair processes by releasing bFGF, beta-NGF, PDGF, and TGF-beta from binding to alpha2M [PMID: 9780213]. Also, TGF-beta and A2M work synergistically to promote proliferation of cultured smooth muscle cells (SMCs) [PMID: 7688745].
-   Cancer resistance is a major cause for longevity of the naked mole-rat. A liver transcriptome analysis in this animal compared to wild-derived mice revealed higher expression of alpha2-macroglobulin (A2M). A2M is known to dramatically decrease with age in humans. A2M modulates tumor cell adhesion, migration and growth by inhibition of tumor promoting signaling pathways, e.g. PI3K / AKT, SMAD and up-regulated PTEN via down-regulation of miR-21. Studies suggest that A2M might play an important role in anti-cancer and the anti-aging mechanisms [PMID: 29281661, PMID: 26103567].
-   Analysis of a deletion in the A2M gene at the 5' splice site of 'exon II' of the bait region (exon 18) revealed that inheritance of the deletion (A2M-2) confers increased risk for Alzheimer disease. A2M has been implicated in Alzheimer disease based on its ability to mediate the clearance and degradation of A beta, the major component of beta-amyloid deposits [PMID: 9697696]. A2M polymorphism, Val1000 (GTC)/Ile1000 (ATC), which occurs near the thiolester active site of the molecule was also associated with AD [PMID: 9811940].

## Summary

Alpha-2-macroglobulin (A2M), encoded by the A2M gene, functions in the bone marrow primarily as a protease inhibitor and a modulator of cytokine activity [CS: 9]. By trapping proteases through its unique bait-and-trap mechanism, A2M regulates protease activity [CS: 9], which is crucial for maintaining the balance between bone formation and resorption, as well as controlling inflammatory responses within the bone marrow environment [CS: 8].

In the bone marrow, A2M dysregulation can be linked to its role in modulating stem cell functions and inflammatory responses [CS: 7]. For instance, the downregulation of A2M in skeletal stem/progenitor cells (SSPCs) from elderly mice correlates with increased adipogenesis at the expense of osteogenesis [CS: 8]. This suggests that A2M normally acts to maintain a balance between fat and bone formation in the bone marrow [CS: 7]. When this balance is disrupted, as in aging or disease, A2M expression changes to counteract these effects, but may inadvertently contribute to bone marrow dysfunction [CS: 7]. Additionally, the upregulation of A2M in response to adrenocorticotropic hormone (ACTH) in osteoblasts indicates a protective response to enhance bone formation, potentially as a countermeasure to bone loss or damage [CS: 7]. In disease states like Alzheimer's disease, where A2M is involved in clearing inflammatory cytokines and A-beta peptides [CS: 6], its upregulation in the bone marrow may reflect a systemic response to inflammation and cellular stress [CS: 7]. These changes in A2M expression in the bone marrow, therefore, appear to be attempts to maintain homeostasis and protect against cellular and tissue damage, but can also contribute to the pathological processes when dysregulated [CS: 7].
