JCI – Bone marrow mesenchymal stem cells and TGF- …
By Dr. Matthew Watson
High levels of active TGF- in the bone marrow and abnormalities in bone remodeling are associated with multiple skeletal disorders. Genetic mutations in the TGF- signaling pathway cause premature activation of matrix latent TGF- and may manifest with various skeletal defects. There are additional diseases that result in high levels of active TGF-, which may contribute to the pathology. Here, we discuss how abnormal TGF- signaling results in uncoupled bone remodeling, mainly by loss of site-directed recruitment of MSCs that causes aberrant bone formation. Direct or indirect inhibition of TGF- signaling may provide potential therapeutic options for these disorders.
Genetic disorders. The critical role of TGF-1 in the reversal phase of bone remodeling is demonstrated by the range of skeletal disorders resulting from mutations in genes involved in TGF-1 signaling. Camurati-Engelmann disease (CED), characterized by a fusiform thickening of the diaphysis of the long bones and skull, is caused by mutations in TGFB1 that result in premature activation of TGF-1 (7174). Approximately 11 different TGFB1 mutations have been identified from families affected by CED (75, 76). All of the mutations are located in the region encoding LAP, either destabilizing LAP disulfide bridging or affecting secretion of the protein, both of which increase TGF-1 signaling, as confirmed by in vitro cell cultures and mouse models. Bone histology sections from patients with CED show decreased trabecular connectivity despite normal bone histomorphometric parameters with respect to osteoblast and osteoclast numbers (76, 77), suggestive of uncoupled bone remodeling. In vitro, the ratio of active to total TGF-1 in conditioned medium from cells expressing the CED mutant TGF-1 is significantly higher and enhances MSC migration (18). Targeted recruitment of MSCs to the bone-remodeling site is likely disrupted, secondary to loss of a TGF- gradient.
Elevations in TGF- signaling have also been observed in many genetic connective tissue disorders with craniofacial, skeletal, skin, and cardiovascular manifestations, including Marfan syndrome (MFS), Loeys-Dietz syndrome (LDS), and Shprintzen-Goldberg syndrome (SGS). MFS is caused by mutations in fibrillin and often results in aortic dilation, myopia, bone overgrowth, and joint laxity. Fibrillin is deposited in the ECM and normally binds TGF-, rendering it inactive. In MFS, the decreased level of fibrillin enhances TGF- activity (78). LDS is caused by inactivating mutations in genes encoding TRI and TRII (79). Physical manifestations include arterial aneurysms, hypertelorism, bifid uvula/cleft palate, and bone overgrowth resulting in arachnodactyly, joint laxity, and scoliosis. Pathologic analyses of affected tissue suggest chronically elevated TGF- signaling, despite the inactivating mutation (79). The mechanism of enhanced TGF- signaling remains under investigation. SGS is caused by mutations in the v-ski avian sarcoma viral oncogene homolog (SKI; refs. 80, 81) and causes physical features similar to those of MFS plus craniosynostosis. SKI negatively regulates SMAD-dependent TGF- signaling by impeding SMAD2 and SMAD3 activation, preventing nuclear translocation of the SMAD4 complex, and inhibiting TGF- target gene output by competing with p300/CBP for SMAD binding and recruiting transcriptional repressor proteins, such as mSin3A and HDACs (8284).
The neurocutaneous syndrome neurofibromatosis type 1 (NF1) has been noted to have skeletal features similar to those of CED, MFS, and LDS, including kyphoscoliosis, osteoporosis, and tibial pseudoarthrosis. Hyperactive TGF-1 signaling has been implicated as the primary factor underlying the pathophysiology of the osseous defects in Nf1fl/Col2.3Cre mice, a model of NF1 that closely recapitulates the skeletal abnormalities found in human disease (85). The exact mechanisms mediating mutant neurofibrominassociated enhancement of TGF- production and signaling remain unknown.
Osteoarthritis. While genetic disorders are rare, they have provided critical insight into the pathophysiology of more common disorders. Uncoupled bone remodeling accompanies the onset of osteoarthritis. TGF-1 is activated in subchondral bone in response to altered mechanical loading in an anterior cruciate ligament transection (ACLT) mouse model of osteoarthritis (86). High levels of active TGF-1 induced formation of nestin+ MSC clusters via activation of ALK5-SMAD2/3. MSCs underwent osteoblast differentiation in these clusters, leading to formation of marrow osteoid islets. Transgenic expression of active TGF-1 in osteoblastic cells alone was sufficient to induce osteoarthritis, whereas direct inhibition of TGF- activity in subchondral bone attenuated the degeneration of articular cartilage. Knockout of Tgfbr2 in nestin+ MSCs reduced osteoarthritis development after ACLT compared with wild-type mice, which confirmed that MSCs are the target cell population of TGF- signaling. High levels of active TGF-1 in subchondral bone likely disrupt the TGF- gradient and interfere with targeted migration of MSCs. Furthermore, mutations of ECM proteins that bind to latent TGF-s, such as small leucine-rich proteoglycans (87) and fibrillin (88), or mutations in genes involved in activation of TGF-, such as in CED (76) and LDS (89), are associated with high osteoarthritis incidence. Osteoblast differentiation of MSCs in aberrant locations appears histologically as subchondral bone osteoid islets and alters the thickness of the subchondral plate and calcified cartilage zone, changes known to be associated with osteoarthritis (90, 91). A computer-simulated model found that a minor increase in the size of the subchondral bone (1%2%) causes significant changes in the mechanical load properties on articular cartilage, which likely leads to degeneration (86). Importantly, inhibition of the TGF- signaling pathway delayed the development of osteoarthritis in both mouse and rat models (86).
MSCs in bone loss. Aging leads to deterioration of tissue and organ function. Skeletal aging is especially dramatic: bone loss in both women and men begins as early as the third decade, immediately after peak bone mass. Aging bone loss occurs when bone formation does not adequately compensate for osteoclast bone resorption during remodeling. Age-associated osteoporosis was previously believed to be due to a decline in survival and function of osteoblasts and osteoprogenitors; however, recent work by Park and colleagues found that mature osteoblasts and osteoprogenitors are actually nonreplicative cells and require constant replenishment from bone marrow MSCs (92). When MSCs fail to migrate to bone-resorptive sites or are unable to commit and differentiate into osteoblasts, new bone formation is impaired. Therefore, insufficient recruitment of MSCs, or their differentiation to osteoblasts, at the bone remodeling surface may contribute to the decline in bone formation in the elderly.
There are multiple hypotheses regarding the decreased osteogenic potential of MSCs during aging. For example, during aging, the bone marrow environment has an increased concentration of ROS and lipid oxidation that may decrease osteoblast differentiation, yet increase osteoclast activity (93, 94). MSCs also undergo senescence, which decreases proliferative capacity and contributes to decreased bone formation (95, 96). Cellular senescence involves the secretion of a plethora of factors, including TGF-, which induces expression of cyclin-dependent kinase inhibitors 2A and 2B (p16INK4A and p15INK4B, respectively; refs. 97).
Microgravity experienced by astronauts during spaceflight causes severe physiological alterations in the human body, including a 1%2% loss of bone mass every month during spaceflight (98). Several studies have shown decreases in osteoblastic markers of bone formation and increases in bone resorption (99101). The underlying molecular mechanisms responsible for the apparent concurrent decrease in bone formation and increase in bone resorption remain under investigation. Work by the McDonald group suggests that bone remodeling may become uncoupled under zero-gravity conditions secondary to decreased RhoA activity and resultant changes in actin stress fiber formation (102). In modeled microgravity, cultured human MSCs exhibit disruption of F-actin stress fibers within three hours of initiation of microgravity; the fibers are completely absent after seven days. RhoA activity is significantly reduced, and introduction of an adenoviral construct expressing constitutively active RhoA can reverse the elimination of stress fibers, significantly increasing markers of osteoblast differentiation (102). Under zero-gravity conditions, RhoA is unable to bind to its receptor, and a sufficient number of MSCs may not be able to migrate correctly to the bone-resorptive site for osteoblast differentiation, ultimately leading to bone loss with every cycle of remodeling.
Bone metastases are a frequent complication of cancer and often have both osteolytic and osteoblastic features, indicative of dysregulated bone remodeling. The importance of the bone marrow microenvironment contributing to the spread of cancer was first described in 1889 (103), postulating that tumor cells can grow only if they are in a conducive environment. Activation of matrix TGF- during bone remodeling plays a central role in the initiation of bone metastases and tumor expansion by regulating osteolytic and prometastatic factors (reviewed in refs. 104110). For example, TGF- can induce osteoclastic bone destruction by upregulating tumor cell expression of PTHrP and IL-11. Additionally, upregulation of CXCR4 by TGF- may home cancer cells to bones.
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JCI - Bone marrow mesenchymal stem cells and TGF- ...
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