Role of protein-tyrosine phosphatases in regulation of osteoclastic activity

Abstract

Osteoclasts, the primary cell type mediating bone resorption, are multinucleated, giant cells derived from hematopoietic cells of monocyte-macrophage lineage. Osteoclast activity is, in a large part, regulated by protein-tyrosine phosphorylation. While information about functional roles of several protein-tyrosine kinases (PTK), including c-Src, in osteoclastic resorption has been accumulated, little is known about the roles of protein-tyrosine phosphatases (PTPs) in regulation of osteoclast activity. Recent evidence implicates important regulatory roles for four PTPs (SHP-1, cyt-PTP-ε, PTP-PEST, and PTP-oc) in osteoclasts. Cyt-PTP-ε, PTP-PEST, and PTP-oc are positive regulators of osteoclast activity, while SHP-1 is a negative regulator. Of these PTPs in osteoclasts, only PTPoc is a positive regulator of c-Src PTK through dephosphorylation of the inhibitory phosphotyrosine-527 residue. Although some information about mechanisms of action of these PTPs to regulate osteoclast activity is reviewed in this article, much additional work is required to provide more comprehensive details about their functions in osteoclasts. KeywordsProtein-tyrosine dephosphorylation; Osteoclast; c-Src; Bone resorption; Protein-tyrosine phosphatases; PTP-oc; cytosolic PTP-ε; PTP-PEST; SHP-1 Bone and bone remodelingBone is a vital, dynamic connective tissue, comprising of a complex mixture of organic and inorganic materials. The large majority of the organic matter is type I collagen that is the basic building block of the bone matrix fiber network. The inorganic matter is composed primarily of calcium phosphate in the form of hydroxyapatite crystals. The cellular component of the bone is made up of three functionally distinct cell types: the first cell type is the osteoblast, which is derived from osteoprogenitor cells of the mesenchymal lineage [1]. Osteoblasts are the principal cell type that mediates bone formation by synthesizing bone matrix and by promoting mineralization of the newly synthesized matrix [1]. The second cell type is the osteocyte, which is the star-shaped, terminally differentiated osteoblast that is fully entrapped by the bone matrix [2]. Osteocytes are well situated within bone matrix to detect mechanical loading stress [3], have the ability to communicate with other bone cells through an extensive

Protein Tyrosine Phosphatase Inhibition by Metals and Metal Complexes

“…In the human genome, there are at least 107 PTP genes, and 81 PTPs of them are active protein phosphatases with the ability to dephosphorylate phosphotyrosine residues (1). PTP activities are dysregulated in many human diseases, including diabetes, obesity, cancer, immune disorders, and osteoporosis (40,46,55,96,116). Protein tyrosine phosphatase 1B (PTP1B) was the first identified and characterized PTP.…”

A novel miR17 /protein tyrosine phosphatase-oc/EphA4 regulatory axis of osteoclast activity

“…Several cellular PTPs have been reported to have modulatory actions on osteoclast formation and/or activity, including SH2 domain-containing PTP-1 (Shp1), dual-specificity phosphatase MAPK phosphatase-1 (MKP1), dual-specificity tyrosine phosphorylation-regulated kinase 2 (Drk2), SH2 domain-containing PTP-2 (Shp2), PTP-PEST (also known as PTPN12), cytosolic PTP-ε, and an osteoclastic protein-tyrosine (PTP-oc). The role of these PTPs in the regulation of osteoclast functions was reviewed elsewhere (65–67). However, this review focuses only on PTP-oc.…”

Molecular biology of bone remodeling: Implications for new therapeutic targets for osteoporosis

“…Also recent studies have established a role of protein tyrosine phosphatases (PTP) in the regulation of osteoclast function and survival. Cyt-PTP-epsilon, PTP-PEST, and PTP-oc are positive regulators of osteoclast activity, while SHP-1 is a negative regulator (34). These molecules are essential for the osteoclast migration and attachment of α V β 3 integrin on osteoclast surface with bone matrix.…”