Bone morphogenetic proteins (BMPs) are members of the TGF-beta superfamily of molecules. They are multifunctional cytokines involved in many aspects of tissue development and morphogenesis. BMP-6 or Vgr-1 (mouse homologue) is an autocrine stimulator of chondrocyte differentiation1 and has been implicated in the development of embryonic kidney and urinary systems.2 It also may be involved in liver growth and differentiation,3 as well as keratinocyte differentiation4 and neural development.5 Recently, BMP-6 expression was found to be localized to muscle cells in the developing human fetal intestine,6 expanding its role as a regulator of developing tissues. Within the BMP family, BMP-6 is grouped together with BMP-5, BMP-7/OP-1, and BMP-8/OP-2 based on the amino acid (aa) sequence comparisons of the carboxy-terminal mature regions. As is characteristic with other members of the TGF-beta superfamily, active, mature BMP-6 is generated by the proteolytic removal of the signal peptide and propeptide, yielding a disulfide-linked homodimeric protein consisting of two 132 aa residue subunits. The predicted MW of each subunit is approximately 15 kDa, but due to glycosylation, the reduced monomer migrates in the range of 18-23 kDa.
BMP-6 expression is tightly regulated in the differentiation of the epidermis. Over- and underexpression of this gene in transgenic mice can result in completely opposite effects, depending on the pattern of expression. Strong uniform expression of the transgene in the suprabasal layers of the epidermis results in severe repression of cell proliferation in both embryonic and perinatal epidermis. In contrast, weak and patchy expression results in strong hyperproliferation as well as parahyperkeratosis in adult epidermis.7 Since cell division is usually restricted to the basal layer of the epidermis, while differentiation takes place in the suprabasal layers, changes in these patterns are seen in many highly prevalent human skin diseases including psoriasis. One explanation for these dose-dependent variable responses of keratinocytes to BMP-6 may be that it is a method of controlling cell proliferation and epidermal thickness in late prenatal and neonatal mice by alternating between stimulation and repression of the epidermal cells. Delayed wound healing was also observed in the transgenic BMP-6 mouse model.8 This delay corresponds to the accumulation of BMP-6 throughout all suprabasal epidermal layers of the chronic wound margin and is consistent with the repression of keratinocyte proliferation during the late stages of wound healing. This may hinder proper re-epithelialization, which would occur under normal conditions.
BMP-6 strongly induces alkaline phosphatase activity in osteoblast MC3T3-E1 cells and myoblast C2C12 cells. It has a receptor binding profile similar to BMP-7 where there is strong binding to Act RI (ALK-2) together with Act RII or BMP RII. BMP-6 also weakly binds to BMP RIA.9 The action of BMP-6 on cells of the osteoblast lineage may be significant, given the fact that bone remodeling, the balance of new bone formation by osteoblasts and bone degradation by osteoclasts, is disturbed in conditions where tumors metastasize to bone. In human prostatic adenocarcinoma, metastases are consistently produced in approximately 90% of cases. Here bone lesions are described as osteoblastic, where new bone formation predominates over bone destruction. Positive signals for BMP-6 mRNA have been observed in the epithelial cells of a majority of primary prostatic carcinomas with established skeletal metastases, whereas it is rarely seen in organ-confined tumors.10 BMP-6 mRNA has also been detected in 11 of 13 bone metastases from prostate carcinoma and in three paired samples of primary prostate carcinoma with matching skeletal metastases.11 This association raises the question of what function BMP-6 may have in the progression of early prostate carcinoma to the advanced metastatic phenotype.
BMP-6 is also a potential regulator for neuronal tissue. Serotonin (5-HT) is only present in a small fraction of neurons in the brain, but is involved in a comprehensive list of autonomic functions, including hunger and body weight, respiration, anxiety, and sleep-wake cycle. Serotonergic neurons are localized in or near the hindbrain raphe region of the brain.12-14 BMP-6 mRNA is prominently expressed in the hindbrain raphe of the embryonic rat. In a serum-free culture of 5-HT neurons isolated from this portion of the brain, BMP-6 mediates the effects of serotonergic development, including cell proliferation and vimentin-positive (serotonergic marker) cells. These effects are inhibited with the addition of TrkB/Fc fusion protein but not with TrkC/Fc fusion protein. Since brain-derived neurotrophic factor (BDNF) mediates its effect through the TrkB receptor, it is possible that BMP-6 acts indirectly on these neurons by stimulating BDNF synthesis or release. In fact, increased levels of BDNF mRNA are detected when BMP-6 is added to these cultures.15
This sampling of observations underscores the fact that BMP-6, along with the other members of this important family of molecules, has widely diverse biological activities in various systems. There is tremendous potential in gaining a better understanding on how these molecules function as regulators of growth and differentiation for a multitude of cell lineages.
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