Source: https://patents.google.com/patent/US5013649A/en
Timestamp: 2018-11-16 19:11:42
Document Index: 711844908

Matched Legal Cases: ['art 1986', 'art 1986', 'art 1987', 'art 1988', 'art 1989', 'art 1989']

US5013649A - DNA sequences encoding osteoinductive products - Google Patents
DNA sequences encoding osteoinductive products Download PDF
US5013649A
US5013649A US07179100 US17910088A US5013649A US 5013649 A US5013649 A US 5013649A US 07179100 US07179100 US 07179100 US 17910088 A US17910088 A US 17910088A US 5013649 A US5013649 A US 5013649A
US07179100
Ground bovine bone powder (20-120 mesh, Helitrex) is prepared according to the procedures of M. R. Urist et al., Proc. Natl Acad. Sci USA, 70:3511 (1973) with elimination of some extraction steps as identified below. Ten kgs of the ground powder is demineralized in successive changes of 0.6N HCl at 4° C. over a 48 hour period with vigorous stirring. The resulting suspension is extracted for 16 hours at 4° C. with 50 liters of 2M CaCl2 and 10 mM ethylenediamine-tetraacetic acid [EDTA], and followed by extraction for 4 hours in 50 liters of 0.5M EDTA. The residue is washed three times with distilled water before its resuspension in 20 liters of 4M guanidine hydrochloride [GuCl], 20mM Tris (pH 7.4), 1 mM N-ethylmaleimide, 1 mM iodoacetamide, b 1 mM phenylmethylsulfonyl fluorine as described in Clin. Orthop. Rel. Res., 171: 213 (1982). After 16 to 20 hours the supernatant is removed and replaced with another 10 liters of GuCl buffer. The residue is extracted for another 24 hours.
The above fractions from the superose columns are pooled, dialyzed against 50mM NaAc, 6M urea (pH4.6), and applied to a Pharmacia MonoS HR column. The column is developed with a gradient to 1.0 M NaCl, 50mM NaAc, 6M urea (pH4.6). Active bone and/or cartilage formation fractions are pooled and brought to pH3.0 with 10% trifluoroacetic acid (TFA). The material is applied to a 0.46×25 cm Vydac C4 column in 0.1% TFA and the column developed with a gradient to 90% acetonitrile, 0.1% TFA (31.5% acetonitrile, 0.1% TFA to 49.5% acetonitrile, 0.1% TFA in 60 minutes at 1 ml per minute). Active material is eluted at approximately 40-44% acetonitrile. Aliquots of the appropriate active fractions are iodinated by one of the following methods: P. J. McConahey et al, Int. Arch. Allerov, 29:185-189 (1966); A. E. Bolton et al, Biochem J., 133:529 (1973) ; and D. F. Bowen-Pope, J. Biol. Chem., 237:5161 (1982). The iodinated proteins present in these fractions are analyzed by SDS gel electrophoresis and urea Triton×100 isoelectric focusing. At this stage, the protein having bone and/or cartilage forming activity is estimated to be approximately 10-50% pure.
Approximately 20 ug protein from Example I is lyophilized and redissolved in 1×SDS sample buffer. After 15 minutes of heating at 37° C., the sample is applied to a 15% SDS polyacrylamide gel and then electrophoresed with cooling. The molecular weight is determined relative to prestained molecular weight standards (Bethesda Research Labs). Immediately after completion, the gel lane containing bone and/or cartilage forming material is sliced into 0.3cm pieces. Each piece is mashed and 1.4ml of 0.1% SDS is added. The samples are shaken gently overnight at room temperature to elute the protein. Each gel slice is desalted to prevent interference in the biological assay. The supernatant from each sample is acidified to pH 3.0 with 10% TFA, filtered through a 0.45 micron membrane and loaded on a 0.46cm×5cm C4 Vydac column developed with a gradient of 0.1% TFA to 0.1% TFA, 90% CH3 CN. The appropriate bone and/or cartilage inductive protein-containing fractions are pooled and reconstituted with 20 mg rat matrix and assayed. In this gel system, the majority of bone and/or cartilage inductive fractions have the mobility of a protein having a molecular weight of approximately 28,000-30,000 daltons.
The isoelectric point of bone inductive factor activity is determined in a denaturing isoelectric focusing system. The Triton X100 urea gel system (Hoeffer Scientific) is modified as follows: 1) 40% of the ampholytes used are Servalyte 3/10; 60% are Servalyte 7-9; and 2) the catholyte used is 40 mM NaOH. Approximately 20 ug of protein from Example I is lyophilized, dissolved in sample buffer and applied to the isoelectrofocusing gel. The gel is run at 20 watts, 10° C. for approximately 3 hours. At completion the lane containing bone and/or cartilage inductive factor is sliced into 0.5 cm slices. Each piece is mashed in 1.0 ml 6M urea, 5 mM Tris (pH 7.8) and the samples agitated at room temperature. The samples are acidified, filtered, desalted and assayed as described above. The major portion of activity as determined by the Rosen-modified Sampath - Reddi assay migrates in a manner consistent with a pI of about 8.8-9.2.
EXAMPLE IV Bovine BMP-2A
Because the genetic code is degenerate (more than one codon can code for the same amino acid), the number of oligonucleotides in a probe pool is reduced based on the frequency of codon usage in eukaryotes, the relative stability of G:T base pairs, and the relative infrequency of the dinucleotide CpG in eukaryotic coding sequences [See J. J. Toole et al, Nature. 312:342-347 (1984)]. Bracketed nucleotides are alternatives. "N" means either A, T, C or G. These probes are radioactively labeled and employed to screen a bovine genomic library. The library is constructed as follows: Bovine liver DNA is partially digested with the restriction endonuclease enzyme Sau 3A and sedimented through a sucrose gradient. Size fractionated DNA in the range of 15-30 kb is then ligated to the vector lambda J' Bam H1 arms [Mullins et al., Nature, 08:856-858 (1984)]. The library is plated at 8000 recombinants per plate. Duplicate nitrocellulose replicas of the plaques are made and amplified according to a modification of the procedure of Woo et al, Proc. Natl. Acad. Sci. USA, 75:368-891 (1978). Probe #1 is hybridized to the set of filters in 3M tetramethylammonium chloride (TMAC), 0.1M sodium phosphate pH6.5, 1 mM EDTA, 5×Denhardts, 0.6% SDS, 100 ug/ml salmon sperm DNA at 48 degrees C., and washed in 3M TMAC, 50 mM Tris pH8.0 at 50 degrees C. These conditions minimize the detection of mismatches to the 17 mer probe pool [see, Wood et al, Proc. Natl. Acad. Sci, U.S.A., 82:1585-1588 (1985)].
EXAMPLE V Human BMP-2A and BMP-2B
The HindIII-SacI bovine genomic BMP-2A fragment described in Example IV is subcloned into an M13 vector. A 32 P-labeled single-stranded DNA probe is made from a template preparation of this subclone. This probe is used to screen polyadenylated RNAs from various cell and tissue sources. Polyadenylated RNAs from various cell and tissue sources are electrophoresed on formaldehyde-agarose gels and transferred to nitrocellulose by the method of Toole et al., supra. The probe is then hybridized to the nitrocellulose blot in 50% formamide, 5×SSC, 0.1% SDS, 40 mM sodium phosphate pH 6.5, 100 ug/ml denatured salmon sperm DNA, and 5 mM vanadyl ribonucleosides at 42° C. overnight and washed at 65° C. in 0.2×SSC, 0.1% SDS. A hybridizing band corresponding to an mRNA species of approximately 3.8 kb is detected in the lane containing RNA from the human cell line U-2 OS. The HindIII-SacI fragment is labeled with 32 P by nick translation and used to screen the nitrocellulose filter replicas of the above-described U-2 OS cDNA library by hybridization in standard hybridization buffer at 65° overnight followed by washing in 1 ×SSC, 0.1% SDS at 65°. Twelve duplicate positive clones are picked and replated for secondaries. Duplicate nitrocellulose replicas are made of the secondary plates and both sets hybridized to the bovine genomic probe as the primary screening was performed. One set of filters is then washed in 1×SSC, 0.1% SDS; the other in 0.1×SSC, 0.1% SDS at 65°.
Two classes of hBMP-2 cDNA clones are evident based on strong (4 recombinants) or weak (7 recombinants) hybridization signals under the more stringent washing conditions (0.1×SSC, 0.1% SDS). All 11 recombinant bacteriophage are plaque purified, small scale DNA preparations made from plate lysates of each, and the inserts subcloned into pSP65 and into M13 for sequence analysis. Sequence analysis of the strongly hybridizing clones designated hBMP-2A (previously designated BMP-2 and BMP-2 Class I) indicates that they have extensive sequence homology with the sequence given in Table I. These clones are therefore cDNA encoding the human equivalent of the protein encoded by the bBMP-2A gene whose partial sequence is given in Table I. Sequence analysis of the weakly hybridizing recombinants designated hBMP-2B (previously designated BMP-4 and BMP-2 Class II) indicates that they are also quite homologous with the sequence given in Table I at the 3' end of their coding regions, but less so in the more 5' regions. Thus they encode a human protein of similar, though not identical, structure to that above.
Full length human BMP-2A cDNA clones are obtained in the following manner. The 1.5 kb insert of one of the BMP-2B subclones (II-10-1) is isolated and radioactively labeled by nick-translation. One set of the nitrocellulose replicas of the U-2 OS cDNA library screened above (50 filters, corresponding to 1,000,000 recombinant bacteriophage) are rehybridized with this probe under stringent conditions (hybridization at 65° in standard hybridization buffer; washing at 65° in 0.2×SSC, 0.1% SDS). All recombinants which hybridize to the bovine genomic probe which do not hybridize to the BMP-2B probe are picked and plaque purified (10 recombinants). Plate stocks are made and small scale bacteriophage DNA preparations made. After subcloning into M13, sequence analysis indicates that 4 of these represent clones which overlap the original BMP-2A clone. One of these, lambda U20S-39, contains an approximately 1.5 kb insert and was deposited with the ATCC on Jun. 16, 1987 under accession number 40345. The partial DNA sequence (compiled from lambda U20S-39 and several other hBMP-2A cDNA recombinants) and derived amino acid sequence are shown below in Table II. Lambda U20S-39 is expected to contain all of the nucleotide sequence necessary to encode the entire human counterpart of the protein BMP-2A encoded by the bovine gene segment whose partial sequence is presented in Table I. The BMP-2A protein encoded by Table II is contemplated to contain the 97 amino acid sequence from amino acid #299 to #396 or a sequence substantially homologous thereto. This human cDNA hBMP-2A contains an open reading frame of 1188 bp, encoding a protein of 396 amino acids. The protein is preceded by a 5' untranslated region of 342 bp with stop codons in all frames. The 13 bp region preceding this 5' untranslated region represents a linker used in the cDNA cloning procedure. This protein of 396 amino acids has a molecular weight of 45 kd based on this amino acid sequence. It is contemplated that this sequence represents the primary translation product. It is further contemplated that BMP-2A may correspond to the approximately 18-20 kd subunit of Example IIC. The sequence corresponding to the sequence tryptic Fragment 3 of Example IV is underlined in Table II.
Hybridization is in standard hybridization buffer AT 50° C. with washing at 50° in 1×SSC, 0.1% SDS. 14 recombinant bacteriophage which hybridize to this oligonucleotide are plaque purified. Plate stocks are made and small scale bacteriophage DNA preparations made. After sucloning 3 of these into M13, sequence analysis indicates that they represent clones which overlap the original BMP-2B clone. One of these, lambda U20S-3, was deposited with the ATCC under accession number 40342 on Jun. 16, 1987. U20S-3 contains an insert of approximately 1.8 kb. The partial DNA sequence and derived amino acid sequence of U20S-3 are shown below in Table III. This clone is expected to contain all of the nucleotide sequence necessary to encode the entire human BMP-2B protein. The BMP-2B protein encoded by Table III is contemplated to contain the 97 amino acid sequence from amino acid #311 to #408 or a sequence substantially homologous thereto. This cDNA contains an open reading frame of 1224 bp, encoding a protein of 408 amino acids, preceded by a 5' untranslated region of 394 bp with stop codons in all frames, and contains a 3' untranslated region of 308 bp following the in-frame stop codon. The 8 bp region preceding the 5' untranslated region represents a linker used in the cDNA cloning procedure. This protein of 408 amino acids has molecular weight of 47 kd and is contemplated to represent the primary translation product. A sequence similar though not identical to tryptic Fragment 3 of Example IV is underlined in Table III.
EXAMPLE VI Expression of BMP-2A and BMP-2B
5'PO.sub.4 -AATTCCTCGAGAGCT 3'
Example VII Biological Activity of Expressed BMP-2A and BMP-2B
(a) nucleotide #1 through nucleotide #387 of figure I,
(b) nucleotide #356 through nucleotide #1543 of figure II,
(c) Nucleotide #402 through nucleotide #1626 of figure III,
(d) naturally occurring allelic sequences and equivalent degenerative codon sequences of (a), (b), and (c); and
(e) sequences which
(1) hybridize to any of sequences (a), (b), (c), or (d) under stringent hybridization conditions; and
(2) encode a protein characterized by the ability to induce the formation of bone and/or cartilage.
2. A vector comprising a DNA sequence of claim 1 in operative association with an expression control sequence for said DNA sequence.
4. A method for producing an osteoinductive protein, said method comprising the steps of
(a) culturing in a suitable culture medium said transformed host cell of claim 3; and
5. The host cell of claim 4 wherein said host cell is a mammalian cell.
US07179100 1986-07-01 1988-04-08 DNA sequences encoding osteoinductive products Expired - Lifetime US5013649A (en)
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ID=58192008
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