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Scientists Discover Cells Responsible For Stone Man Syndrome

Scientists at the University of Connecticut recently published work in Nature Communications (Lees-Shepard et al. 2018, NatComms 9, 471) that describes the discovery of the cell type that is responsible for fibrodysplasia ossificans progressiva (FOP), a rare genetic disease in which skeletal muscle tissue and connective tissues, such as tendons and ligaments, are gradually replaced with bone.

This bone growth, which is called heterotopic ossification (bone forming in the wrong places, separate from the normal skeleton), can be triggered by minor bumps encountered in everyday living, by immunizations, dental work, and other minor tissue damage that is inconsequential to normal individuals. In addition, new bone lesions often occur without known triggers (this is sometimes called spontaneous heterotopic ossification).

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Disease onset typically occurs in early childhood and bone formation is progressive and cumulative. There are no approved disease-altering therapies for FOP, and unwanted bone cannot be removed surgically, as this will trigger new explosive bone growth. FOP patients suffer progressive and life-long severe disability as a cumulative consequence of broadly distributed abnormal bone growth. This ‚Äúsecondary skeleton‚ÄĚ interferes with skeletal muscle function¬†and results in the locking of major and minor joints, spinal fusions, and other complications that together dramatically decrease the quality of life, interfere with activities of daily living, and result in premature death. Because of the body rigidity and immobility caused by the encasing secondary skeletal, FOP is sometimes referred to as Stone Man Syndrome.

Credit: Joh-co/Wikimedia Commons licensed under CC-BY-SA 3.0

In 2006, the genetic cause of FOP was discovered by researchers at the University of Pennsylvania School of Medicine. Remarkably, in their landmark study (Shore et al. 2006, Nature Genetics 38: 525), and in follow-up clinical studies by several groups, it was determined that the overwhelming majority of FOP cases are caused by a single amino acid change in the cell surface receptor ACVR1.

Almost a decade later, independent research teams at Regeneron (Hatsell et al. 2015, Sci Transl Med 7: 303) and Kyoto University (Hino et al. 2015, PNAS 112: 15438) made the groundbreaking discovery that in FOP, a normally inhibitory protein, activin, instead becomes a powerful stimulator of the mutated cell surface receptor. When activin protein in the tissue environment binds to the mutant receptor, molecular signals are transmitted to the interior of the cell, instructing the cell to make bone. Until recently, however, the identity of the cells responsible for the disease was unknown.

Identification of the disease-causing receptor allowed University of Connecticut researchers to use genetic engineering to produce mice that carry the identical FOP mutation. Using cell marking methods (sometimes called lineage tracing) together with cell sorting techniques, the research team identified the culprit, a cell known as the fibro/adipogenic progenitor (FAP). Remarkably, FOP mice that express the mutant receptor specifically in FAPs recapitulate all major aspects of human FOP, including both injury-induced and spontaneous disease, and heterotopic ossification at essentially all anatomical sites described for FOP patients. The involvement of FAPs in FOP was unexpected, as FAPs, which had been independently identified in earlier studies, were well known for their ability to make connective tissues and fat, but their robust bone-forming capacity was not known.

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Under normal physiological conditions, injured skeletal muscle has an enormous capacity to regenerate, which restores its normal structure and function. Regeneration is mediated by muscle-specific stem cells called satellite cells, and some evidence indicates that the normal physiological function of FAPs is to facilitate satellite cell-driven regeneration. In FOP, however, the developmental trajectory of skeletal muscle is altered such that injury stimulates new bone growth rather than eliciting a robust muscle regenerative response. Investigators are now trying to understand how a single amino acid change in a receptor expressed by FAPs instructs them to make bone and how this cell reprogramming inhibits the muscle regenerative process. If researchers can understand this problem in developmental biology, they may be able to intervene therapeutically with targeted, cell-specific therapies that block the pathological course that FAPs adopt in FOP.

While heterotopic ossification reaches its most extreme form in FOP, it can also result from certain types of soft tissue injuries and surgeries. In fact, in the general population, epidemiological studies have estimated a 10-20% incidence of heterotopic ossification following traumatic injury, and injuries as varied as central nervous system damage, deep tissue sports injuries, total hip replacement, and burns are apparent triggers. In addition, among military personnel, heterotopic ossification is a well-described and common consequence of blast wounds to the extremities. Although additional research is required to determine the extent to which FAPs are responsible for these non-genetic cases of heterotopic ossification, it is anticipated that lessons learned from studies of FOP and FAP biology will be more broadly applicable to heterotopic ossification in the general population.

These findings are described in the articles entitled, Stem cells and heterotopic ossification: Lessons from animal models, recently published in the journal Bone (Lees-Shepard and Goldhamer 2018, Bone 109,  178) and Activin-dependent signaling in fibro/adipogenic progenitors causes fibrodysplasia ossificans progressiva, recently published in the journal Nature Communications (Lees-Shepard et al. 2018, NatComms 9, 471). The work on cells responsible for FOP was conducted by the research team led by David J. Goldhamer from the University of Connecticut.

Comment (1)

  1. I’m just trying to better understand…

    The majority of FOP cases are caused by a single amino acid change in the cell surface receptor ACVR1.

    In FOP, activin becomes a powerful stimulator of the mutated cell surface receptor ACVR1. When activin protein in the tissue environment binds to the mutant receptor, molecular signals are transmitted to the interior of the cell, instructing the cell to make bone.

    From Wikipedia – https://en.wikipedia.org/wiki/ACVR1
    “A mutation in the gene ACVR1 (= ALK2) is responsible for the fibrodysplasia ossificans progressiva. ACVR1 encodes activin receptor type-1, a BMP type-1 receptor. The mutation causes the ACVR1 protein to have the amino acid histidine substituted for the amino acid arginine at position 206. This causes the protein ALK2 to change in the critical glycine-serine activation domain of the protein which will cause the protein to bind its inhibitory ligand (FKBP12) less tightly, and activate its SMAD pathway specific proteins more effectively than usual. The result is the BMP pathway will trigger when it should not, and bone will form in soft tissues throughout the body. This causes endothelial cells to transform to mesenchymal stem cells and then to bone.”

    “Skeletal muscle fibro-adipogenic progenitors of dystrophic mice are insensitive to NOTCH-dependent regulation of adipogenesis”:
    https://www.biorxiv.org/content/10.1101/223370v1
    An unbiased mass spectrometry-based proteomic analysis of FAPs from muscles of wild type and mdx mice, revealed that the synergistic cooperation between NOTCH and inflammatory signals controls FAP differentiation. These results offer a basis for rationalizing the pathological outcomes of fat infiltrations in skeletal muscle and may suggest new therapeutic strategies to mitigate the detrimental effects of fatty depositions in muscles of dystrophic patients.

    “Notch signaling pathway”:
    https://en.wikipedia.org/wiki/Notch_signaling_pathway
    Notch signaling promotes proliferative signaling during neurogenesis, and its activity is inhibited by Numb to promote neural differentiation. It plays a major role in the regulation of embryonic development. Notch signaling also has a role in the expansion of the hematopoietic stem cell compartment during bone development and participation in commitment to the osteoblastic lineage.

    My thought:
    Perhaps the cases of non-FOP-affected people who have experienced repeated traumatic injuries that result in ectopic bone formation have cellular activities similar to those resulting from the mutated FOP cell surface receptor ACVR1.

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