Non-Collagenous Proteins of Bone
April 13, 2008 by Dr Arun Pal Singh
Filed under Musculoskeletal Anatomy
Non-collagenous proteins of bone are a heterogeneous group which vary from entrapped serum protein to glycoproteins, which are unique to bone and which probably play a role in mineralization.
Osteocalcin
Osteocalcin or bone Gla protein (BGP) is the best characterized of the non-collagenous proteins of bone and it makes up between 10 and 20 percent of them. Its amino acid sequence is very well preserved across the vertebrate phylogenetic tree, suggesting that it plays an important role but this is as yet unelucidated.
It is synthesized by the osteoblast as a 99 amino acid propeptide which is then cleaved to leave a 50 amino acid protein which is secreted.
Osteocalcin is produced only by osteoblasts and a proportion of the newly synthesized protein escapes into the serum. Raised serum levels of osteocalcin have been reported in diseases which are associated with increased bone turnover such as Paget’s disease, renal osteodystrophy and primary hyperparathyroidism.
This has led to interest in the measurement of osteocalcin as a biochemical marker of bone formation. However, due partly to difficulty with osteocalcin assays, the exact significance of serum measurements has yet to be elucidated.
Matrix Gla Protein
As much as 50 percent of the total glutamic acid containing proteins of bone are distinct from osteocalcin. The best characterized of these is matrix Gla protein (MGP), a 10,000 Da protein found in association with bone morphogenetic protein (BMP).
Osteonectin
A number of phosphoproteins and glycoproteins are found in bone. The phosphate is bound to the protein backbone through serine or threonine amino acid residues. The best characterized of these bone protein is osteonectin. It binds collagen and hydroxyapatite through separate areas of its molecule, is found in relatively large amounts in immature bone and promotes mineralization of collagen. Thus it is possible that osteonectin plays a crucial role in mineralization.
Proteoglycans
Bone proteoglycan has a small protein core with up to two chondroitin sulphate chains attached. They constitute approximately 10 percent of the non-collagenous proteins of bone. Their role is unclear.
The sulphated glycosaminoglycans in connective tissue are chondroitin sulphate, keratan sulphate and dermatan sulphate. They are bound at one end to a protein core; e.g., 50-100 chondroitin sulphate chains are attached laterally by the sac-charide sequence of neutral sugars to the core protein, giving a molecular weight of about 1-3 X 106. Proteoglycans are particularly vulnerable to proteolytic enzymes, with the whole molecule breaking up when a few peptide bonds are split off.
Some keratan sulphate chains are also Attached to the same protein core. It should be noted that in cartilage the proteoglycan population is heterogeneous, varying in chemical composition and size of their molecules.
Chondoitin sulphate consist of disaccharide units of glucuronic acid and N-acetylgalactosamines with sulphate residues. Keratan sulphate has in its structure galactose instead of glucuronic acid, with varying amounts of sulphate.
The elasticity and resilience of cartilage results from this matrix of proteoglycans, collagen and water. They have demonstrated how the compressive stiffness of cartilage over short intervals directly correlates to the presence of proteoglycans when measured as glycosaminoglycans.
Because of this, as a load is applied to cartilage there is an increase in the fluid pressure and water is driven out, but the cartilage deforms only slowly. Maroudas (1975) described the internal osmotic pressure of human femoral cartilage as being about 3.4-3.6 atmospheres (343.4-363.6 kPa).
The proteoglycans have a very significant role in controlling swelling, pressure and the movement of water molecules when cartilage is placed under load.
In cartilage, most proteoglycans are in the form of large (200 000 kDa or more) aggregates that provide the tissue with its resilience under compressive loads. The basic structure of the cartilage proteoglycan aggregate has been well established by biochemical methods and molecular biological techniques.
It is constructed from glycosaminoglycan chains attached to core protein molecules which are themselves attached to hyaluronic acid under the stabilizing influence of link of protein. Although most recent studies of cartilage proteoglycan have dealt with articular cartilage,e such data re not uniformly transposable to the growth plate.
The interaction of link protein with proteoglycan monomer and hyaluronic acid from bovine fetal epiphyseal cartilage was recently characterized. The proteoglycan monomers from this cartilage are almost aggregating monomers. As expected, link protein substantially increased the percentage of aggregating monomers.
Proteoglycan aggregate stability was found to be highly pH-dependent: decreasing the pH form 5 to 4 in the absence of link protein resulted in essentially complete aggregate dissociation. Link protein was protective against much of the pH-induced instability. Optimization of both pH and link protein increased not only the stability of the aggregate but also its size.
In addition to their contribution to matrix structure, proteoglycans in the growth plate may play a role in mineralization. Focal concentrations of proteoglycan at the sites of mineralization are well documented.
Because the chondroitin sulphate chains of progeoglycans bind calcium and because phosphate can displace this calcium from the proteoglycans, proteoglycan may serve as the medium within which calcium release by ion exchange could raise the Ca X PO¬4 product above the threshold for hydroxyapatite precipitation.
Sialoprotein
These are glycoporteins containing the sugar N-acetylneuraminic acid (sialic acid). The make up approximately 7.5 percent of the total non-collagenous protein of bone and their function is unclear.
Serum proteins
These constitute the largest number of non-collagenous proteins in bone. They include serum albumin and some immunoglobulins. They constitute approximately a quarter of the total non-collagenous protein and their function is unknown.
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