The role of matrix metalloproteinases (MMPs) in osteoclast biology is ill-defined, but in other tissue they have been linked with tumor promoting activities, such as activation of growth factors and are required for tumor metastasis and angiogenesis. MMP9 is associated with the bone microenvironment. It is expressed by osteoclasts, and is known to be required for osteoclast migration and is a powerful gelatinase. Transgenic mice lacking MMP-9 develop defects in bone development, intraosseous angiogenesis, and fracture repair. MMP-13 is believed to be involved in bone resorption and in osteoclast differentiation, as knockout mice revealed decreased osteoclast numbers, osteopetrosis, and decreased bone resorption. MMPs expressed by the osteoclast include MMP-9, -10, -12, and -14. apart from MMP-9, little is known about their relevance to the osteoclast, however, high levels of MMP-14 are found at the sealing zone. Osteoclast physiology
In the 1980s and 90s the physiology of typical osteoclasts was studied in detail. With the isolation of the ruffled border, ion transport across it was studied directly in biochemical detail. Energy-dependent acid transport was verified and the postulated proton pump purified. With the successful culture of osteoclasts, it became apparent that they are organized to support the massive transport of protons for acidification of the resorption compartment and solubilization of the bone mineral. This includes ruffled border Cl− permeability to control membrane potential and basolateral Cl−/HCO3− exchange to maintain cytosolic pH in physiologically acceptable ranges.The effectiveness of its ion secretion depends upon the osteoclast forming an effective seal around the resorption compartment.
Function
Once activated, osteoclasts move to areas of microfracture in the bone by chemotaxis. Osteoclasts lie in small cavities called Howships lacunae, formed from the digestion of the underlying bone. The sealing zone is the attachment of the osteoclasts plasma membrane to the underlying bone. Sealing zones are bounded by belts of specialized adhesion structures called podosomes. Attachment to the bone matrix is facilitated by integrin receptors, such as αvβ3, via the specific amino acid motif Arg-Gly-Asp in bone matrix proteins, such as osteopontin. The osteoclast releases hydrogen ions through the action of carbonic anhydrase (H2O + CO2 → HCO3− + H+) through the ruffled border into the resorptive cavity, acidifying and aiding dissolution of the mineralized bone matrix into Ca2+, H3PO4, H2CO3, water and other substances. Dysfunction of the carbonic anhydrase has been documented to cause some forms of osteopetrosis. Hydrogen ions are pumped against a high concentration gradient by proton pumps, specifically a unique vacuolar-ATPase. This enzyme has been targeted in the prevention of osteoporosis. In addition, several hydrolytic enzymes, such as members of the cathepsin and matrix metalloprotease (MMP) groups, are released to digest the organic components of the matrix. These enzymes are released into the compartment by lysosomes. Of these hydrolytic enzymes, cathepsin K is of most importance. Cathepsin K and other cathepsins
Cathepsin K is a collagenolytic papain-like cysteine protease that is mainly expressed in osteoclasts, and is secreted into the resorptive pit. Cathepsin K is the major protease involved in the degradation of type I collagen and other noncollagenous proteins.