Cytokines can be classified into six categories based on biological function: interleukins, interferons, tumor necrosis factors, colony-stimulating factors, chemokines, and growth factors. Bone morphogenetic proteins (BMPs) belong to the transforming growth factor (TGF-β) superfamily. They are involved in vital processes spanning from lower invertebrates to higher mammals, regulating embryonic development (such as bone formation) and adult tissue repair (such as fracture healing), and are associated with diseases like osteoporosis and tumors.

I. Evolutionary History of the BMP Family

1. Origin and Early Evolution: Based on gene sequence comparisons, the BMP family likely originated in primitive eukaryotes (e.g., unicellular green algae) approximately 1 billion years ago. Early members contained only C-terminal functional domains, regulating cell proliferation. Following the emergence of multicellular organisms, the genes acquired N-terminal signal peptides, enabling extracellular secretion and participation in intercellular signaling.

2. Conservation and Specificity Across Species:

• Core Sequence Conservation: The BMP family comprises over 20 members in vertebrates (humans, mice), with 70%-90% homology in the C-terminal TGF-β domain (e.g., 89% homology between human BMP2 and mouse homologs). This ensures stable core functions such as bone induction and embryonic morphogenesis.
• Functional Specificity:
• • Vertebrates (e.g., humans): Highly differentiated functions, such as BMP2/7 governing bone formation and BMP4/5 directing embryonic neural and limb development.
  • Arthropods (e.g., Drosophila): Homologous genes (e.g., Dpp) primarily establish body axis polarity and wing morphology.
  • Nematodes (e.g., Caenorhabditis elegans): Homologous genes (e.g., DBL-1) primarily regulate fundamental traits like body size.

3. Key evolutionary junctures: Vertebrate transition from aquatic to terrestrial environments drove iterative evolution of "bone-inducing subtypes" (BMP2, BMP7), optimizing receptor binding sites for skeletal support demands; mammalian viviparity spurred evolution of BMP15 and GDF9 to regulate follicular development.

Figure 1. Sequence homology alignment and protein structure superposition of the BMP family [1]

II. Molecular Classification of the BMP Family

Traditional BMP nomenclature is based on discovery sequence, but classification based on molecular characteristics more clearly reveals functional relationships. Currently, the BMP family can be refined according to the following criteria:

1. Classification Based on Sequence Homology and Phylogenetic Analysis

By constructing phylogenetic trees, the BMP family can be primarily divided into the following subfamilies:

• BMP2/4 Subfamily: Includes BMP2 and BMP4, the most extensively studied members with the strongest osteogenic activity.
• BMP5/6/7/8 Subfamily (also known as the Osteogenic Protein-1, OP-1 Subfamily): Includes BMP5, BMP6, BMP7, BMP8a, and BMP8b. They play a significant role in skeletal and cartilage development.
• BMP9/10 Subfamily: As ligands with high circulating concentrations in blood, they are key regulators of vascular endothelial cell function.
• Growth and Differentiation Factors (GDF) Subfamily: Includes GDF5, GDF6, and GDF7, which play specific roles in joint, tendon, and ligament development.
• Other members: Such as BMP3, a unique negative regulator that antagonistically functions against other pro-ossification BMPs.

Figure 2. Phylogenetic analysis of the human BMP family members [2]

2. Classification based on propeptide domain differences

BMPs comprise an N-terminal signal peptide, a propeptide domain, and a mature C-terminal ligand domain. The propeptide is crucial for protein folding, secretion, and activity regulation. Based on propeptide structural features, BMPs can be classified as:

• BMPs with "long" propeptides: Examples include the GDF subfamily, whose propeptides contain additional cysteine residues potentially involved in unique disulfide bond formation and protein activation regulation.
• BMPs with "typical" propeptides: e.g., BMP2/4, whose propeptide structures are relatively standard.

3. Classification based on signaling characteristics

• Activators of the canonical BMP pathway: e.g., BMP2/4/7, primarily activate Smad1/5/8 through type I receptors ALK3/BMPR-IA or ALK6/BMPR-IB and type II receptors.
• Non-canonical pathway activators/hybrid: Some BMPs (e.g., BMP9/10) exhibit high affinity for type I receptor ALK1, activating not only Smad1/5/8 but also cross-regulating TGF-β/Activin pathways, reflecting signaling complexity. This receptor selectivity difference constitutes a crucial molecular basis for functional specificity.

This precise classification directly correlates with functional specificity. For example, the BMP2/4 subfamily dominates early embryonic dorsal-ventral patterning and skeletal induction, while the GDF subfamily (e.g., GDF5) more finely regulates morphogenesis at limb tips. This indicates that evolutionary differentiation drives a shift in function from broad, foundational patterning to localized, precise tissue-specific regulation.

III. Molecular characteristics and evolutionary significance of the newly discovered BMP subtype

With advances in genome sequencing technology, several novel BMP-related genes have been identified in non-model organisms and vertebrates, offering new insights into the evolution of the BMP family.

1. Discovery of Novel Subtypes: In model organisms such as zebrafish and African clawed frogs, additional copies of BMP genes absent in mammals have been identified. These result from a third genome duplication event unique to fish. For example, zebrafish possesses two BMP2 genes (bmp2a and bmp2b) that exhibit subfunctionalization, expressing in distinct tissues and performing partial functions.

2. Molecular Characteristics: These novel subtypes often exhibit minor key amino acid variations in mature peptide regions. This may alter their binding properties with receptors or extracellular antagonists (e.g., Noggin, Chordin), thereby adapting to specific physiological or developmental requirements.

3. Evolutionary Significance:

• Species Adaptive Evolution: The emergence and functional differentiation of new BMP subtypes may constitute the genetic basis for species adaptation to diverse environments and the evolution of unique morphological traits (e.g., fin diversity in fish).
• Functional Redundancy and Innovation: Gene duplication provides raw material for functional innovation. One gene copy may maintain the original function (functional redundancy), while another copy has the opportunity to accumulate mutations and acquire new functions (neofunctionalization), thereby increasing organismal complexity.
• Revealing Core Functions: By comparing the functions of BMP paralogs and orthologs across species, we can more precisely delineate which functions are the most core and conserved within the BMP family and which represent derived traits acquired during evolution.

IV. Synthesis and Future Outlook

The evolution of the BMP family follows a "core conservation, functional differentiation" pattern: the highly conserved TGF-β domain maintains fundamental signaling functions, while subtle variations such as propeptide diversity and receptor preferences drive specialized functions in skeletal, neural, vascular, and other domains. The current classification system based on structure and signaling lays the foundation for precision-targeted research.

Future research priorities include: advancing BMP studies in lower organisms; accelerating clinical validation of novel subtypes; and elucidating cross-talk mechanisms with pathways like Wnt. Leveraging cutting-edge technologies such as single-cell sequencing and gene editing will deepen our understanding of BMP networks and open new therapeutic avenues for related diseases.

V. Yeasen BMP Series Cytokines

Recombinant proteins have found extensive applications in core fields such as stem cell and organoid culture, recombinant protein therapeutics, CAR-T cell therapy, and antibody drugs. Amid the rapid expansion of the biopharmaceutical industry, the recombinant protein market is experiencing explosive growth, with demand for high-end raw materials rising annually. To precisely address the continuously evolving application needs in both research and industrial settings—particularly critical pain points like low protein activity and inconsistent batch stability—Yeasen Biotech leverages years of R&D and production expertise to establish an innovative recombinant protein expression and purification platform. This platform focuses on delivering high-activity recombinant protein products. Leveraging its proprietary expression and purification platform, Yeasen Biotech has developed the BMP series HiActi™ cytokines, including BMP-2, BMP-4, and BMP-7. These products undergo rigorous quality control and cellular function validation to ensure high activity, high purity, high stability, and low endotoxin levels, helping you achieve optimal experimental results.

Product Data

Bioactivity of Human BMP-2

Figure 3. The ED50 as determined by inducing alkaline phosphatase production in murine ATDC5 cells is 200 ng/mL, corresponding to a specific activity of > 5.0 × 10³ IU/mg.

Bioactivity of Human BMP-4

Figure 4. The ED50 as determined by inducing alkaline phosphatase production of murine ATDC5 cells is 95 ng/mL.

Ordering Information

Product Name	Catalog Number
Recombinant Human BMP-2 Protein, His Tag	92060ES
Recombinant Human/ Rhesus macaque/Mouse/Rat/Canine BMP2 Protein	95644ES
Recombinant Human BMP-3 Protein	92052ES
Recombinant Human BMP-4 Protein, His Tag	92070ES
Recombinant Mouse BMP-4 Protein, His Tag	92056ES
Recombinant Human BMP-5 Protein, His Tag	92061ES
Recombinant Human BMP-6 Protein, His Tag	92062ES
Recombinant Human BMP-7 Protein	92054ES
Recombinant Human BMP-8a Protein, His Tag	92063ES
Recombinant Human BMP-8b Protein, His Tag	92064ES
Recombinant Human GDF-2/BMP-9 Protein	92059ES
Recombinant Human BMP-10 Protein, His Tag	92065ES
Recombinant Human BMP-11/GDF-11 Protein, His Tag	92066ES
Recombinant Human GDF-7/BMP-12	92001ES
Recombinant Mouse GDF-7/BMP-12	92004ES
Recombinant Human GDF-6/BMP-13	92002ES
Recombinant Human GDF-5/BMP-14	92003ES
Recombinant Mouse GDF-5/BMP-14	92005ES
Recombinant Human BMP-15 Protein, His Tag	92067ES
Recombinant Human BMP-16 Protein, His Tag	92068ES

References

1. Chen H, Zhou Y, Dong Q. Structural Mapping of BMP Conformational Epitopes and Bioengineering Design of Osteogenic Peptides to Specifically Target the Epitope-Binding Sites.  Cellular and Molecular Bioengineering 2022; 15(4):341-352.

2. Wang RN, Green J, Wang Z, Deng Y, Qiao M, Peabody M, et al. Bone Morphogenetic Protein (BMP) signaling in development and human diseases. 2014; 1(1):87-105.