TGF-beta superfamily is a large family of multifunctional proteins that regulate a variety of cellular functions including cellular proliferation, migration, differentiation and apoptosis.
Members of the transforming growth factor beta (TGF-beta) superfamily of proteins are involved in embryonic development and adult tissue homeostasis. The TGF-beta superfamily members share a common strucutre incluidng a peptide signal sequence required for secretion of the protein and an amino-terminal fragment that is proteolytically cleaved about 105-140 amino acids from the carboxyterminus of the large precursor protein to produce the mature protein. The mature protein is characterized by highly conversed cysteine residues, while the active form of the mature protein is a disulfide linked homodimer of the proteoytically cleaved proporotein. (Davies, WO 2007/047112).
Members of the TGF-beta Super family
TGF-beta is the founding member and has been shown to play a vareity of rolles ranging from embryonice pattern formation to cell growth regulation in adult tissues. It exerts is functions by signal transduction cascades that ultimately activate and/or suppress expression of a set of specific genes.
Myostatin (growth differentiation factor-8 (GDF-8): is a member of the TGF-beta superfamily. It is expressed largerely in developing and adult skeletal muscle and functions as a negative regulator of skeletal muscle. Systemic over-expression of myostatin in adult mice leads to muscle wasting, whiche conversely, a myostatin knock out mouse is characterized by hypertrophy and hyperplasia of the skeletal muscle resulting in two to threefold greater muscle mass. (Davies, WO 2007/047112).
Myostatin is a screted growth factor which negatively regulates muscle mass. Loss of funciton mutations in the Myostatin gene, leading to a hypermuscular phenotype, have been described in cattle, sheep, fish, dogs and humans. Myostatin expression is generally limited to skeletal muscle, with low levels of expression reported in adipose and cardiac tissues. Inhibition of Myostatin signaling leads to an increase in muscle size. (Carven, US Patent No: 10,751,413).
Carven, (US Patent No: 10,751,413) discloses antibodies that specifically bind to forms of Myostatin and inhibit its signaling to treat diseases related to ageing such as sarcopenia (age-related muscle loss), fraility and androgen deficiency.
Growth differentation factors (GDFs)
activins
inhibins
Bone Morphogenic Proteins (BMPs)