Lead alters parathyroid hormone‐related peptide and transforming growth factor‐β1 effects and AP‐1 and NF‐κKB signaling in chondrocytes

Zuscik, Michael J.; Pateder, Dhruv B.; Puzas, J. Edward; Schwarz, Edward M.; Rosier, Randy N.; O’Keefe, Regis J.

doi:10.1016/s0736-0266(02)00007-4

Cited by 37 publications

(32 citation statements)

References 48 publications

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“…Since BMP signaling is essential for chondrocyte maturation, it is possible that the effect is secondary to downregulation of this signaling pathway, as was observed in vitro. Thus, although Pb stimulates chondrogenesis, it reduces chondrocyte maturation and thereby results in delayed endochondral bone formation, as has been previously documented (112). Consistent with these in vitro and in vivo data, Pb exposure has been found to inhibit fracture healing in mice, with complex effects noted on chondrogenesis and chondrocyte maturation (113).…”

Section: The Influence Of Pathologic Stress On Chondrogenesis and Endsupporting

confidence: 69%

Regulation of chondrogenesis and chondrocyte differentiation by stress

Zuscik¹,

Hilton²,

Zhang³

et al. 2008

J. Clin. Invest.

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218

173

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Chondrogenesis and endochondral ossification are the cartilage differentiation processes that lead to skeletal formation and growth in the developing vertebrate as well as skeletal repair in the adult. The exquisite regulation of these processes, both in normal development and in pathologic situations, is impacted by a number of different types of stress. These include normal stressors such as mechanical loading and hypoxia as well pathologic stressors such as injury and/or inflammation and environmental toxins. This article provides an overview of the processes of chondrogenesis and endochondral ossification and their control at the molecular level. A summary of the influence of the most well-understood normal and pathologic stressors on the differentiation program is also presented. Introduction to cartilageCartilage is a connective tissue that is comprised primarily of matrix (mainly collagens and proteoglycans) containing relatively sparse populations of chondrocytes, which perform matrix-generation and maintenance functions. During the development and growth of vertebrates, chondrogenesis is the dynamic cellular process that leads to the establishment of various types of cartilage, including hyaline, fibrous, and elastic cartilage. Hyaline cartilage is found in craniofacial structures, the trachea and bronchial tubes, the articular surfaces of diarthrodial joints, and the growth plate (GP) of long bones. GPs are responsible for driving the process of limb lengthening and bone growth during development pre- and postnatally. This type of bone growth involves the process of endochondral ossification (otherwise known as bone formation). The type of cartilage that is most prominent and most susceptible to both normal and pathologic forms of stress is the hyaline cartilage of the limb and trunk skeleton, which originates from the differentiation of condensed mesenchymal cells into clusters of cartilage cells known as chondrocytes. These cartilage anlagen preform the skeleton and provide a framework for endochondral bone development, a process that involves chondrocyte maturation and matrix mineralization in the GPs. The cells of each skeletal element proceed through a multi-step differentiation process generating both the mature GP cartilage, which controls skeletal growth during early and adolescent development, and the permanent articular cartilage (AC) found at the joint surface of all long bones.The processes of chondrogenesis and endochondral bone formation are not restricted to the developing skeletal system. In fact, following stress-related injuries, such as fractures of endochondral bone, the developmental programs of chondrogenesis and chondrocyte proliferation, maturation, hypertrophy, and terminal differentiation are reinitiated at the site of injury. Additionally, stress-related cartilage diseases such as osteoarthritis (OA) also have marked effects on the differentiation and maintenance of AC during adult life. This is why much attention has been paid to studying the cellular and molecular mechanism...

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Section: The Influence Of Pathologic Stress On Chondrogenesis and Endsupporting

confidence: 69%

Regulation of chondrogenesis and chondrocyte differentiation by stress

Zuscik¹,

Hilton²,

Zhang³

et al. 2008

J. Clin. Invest.

Self Cite

218

173

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“…This study demonstrates that environmental exposure to osteotoxic substances results in contamination levels measurably present in bone graft regardless of the source. Animal studies have suggested that comparable degrees of lead exposure have toxic effects on skeletal tissue and fracture healing [3,4,6,15,16,18,[20][21][22][23]. In addition, clinical studies are present in the literature demonstrating deleterious effects on bone healing, bone remodeling, and skeletal development [5,12,14].…”

Section: Discussionmentioning

confidence: 99%

Allogeneic and Autogenous Bone Grafts Are Affected by Historical Donor Environmental Exposure

Behrend

Carmouche

Millhouse

et al. 2016

Clinical Orthopaedics &Amp; Related Research

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Background Bone graft materials are routinely evaluated for infectious agents; however, data regarding contamination of bone graft from environmental exposure of the donors to osteotoxic substances such as lead are not routinely available. In animal models, stored lead in bone has been shown to impair fracture healing and osteocyte function. In clinical studies, lead is linked to skeletal disease at relatively low concentrations. Presumably the levels of lead in allografts mirror the level of lead in bone in the population; however, the degree to which processing might decrease this and the frequency with which potentially osteotoxic levels appear in bone grafts have not been studied. Questions/purposes (1) Does processing of donor bone for allografts result in lower concentrations of lead in commercial allograft when compared with autologous bone graft; and (2) what proportion of bone grafts contain potentially osteotoxic levels of lead from[2.0 to 20.0 lg/g corresponding to environmental exposure? Methods Allograft from commercial sources and autologous bone graft materials were examined for lead content using ICP-atomic absorption spectrophotometric analysis. We analyzed bone graft specimens from 42 donors, including 26 corticocancellous tibial specimens from commercially available bone graft materials and 16 autograft corticocancellous tibial specimens. Lead levels were determined for the cortical (n = 42) and cancellous (n = 42) portions of each specimen. For quality control, all instru-

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“…2,3,46,51 Similarly, alterations in PTHrP signaling can have effects on transforming growth factor-beta and can lead to functional changes in activator protein-1, nuclear factor-B, E26 transformation-specific sequence-1, and specificity protein-1 signaling. 32,34 PTHrP also can inhibit the apoptotic effects of functional mutations in fibroblast growth factor, resulting in decreases in Bcl-2 expression and apoptosis. 52 Finally, PTHrP can be a potent tumor angiogenic factor.…”

Section: Discussionmentioning

confidence: 99%

Parathyroid hormone–related protein expression is correlated with clinical course in patients with glial tumors

Pardo

Lien

Fox

et al. 2004

Cancer

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BACKGROUNDParathyroid hormone–related protein (PTHrP) expression modulates cell survival in a number of human solid tumors. Although PTHrP is expressed in normal developing and neoplastic central nervous system tissue, clinical data indicating the importance of this protein with respect to local control and/or survival in patients with glial tumors are scarce.METHODSUsing a standard immunoperoxidase technique, the authors examined PTHrP expression in a population of 51 patients with Daumas–Duport Grade II–IV astrocytomas over a 15‐year period. Both local control and survival were calculated from the date of definitive irradiation to the last time of known follow‐up examination using the actuarial method. PTHrP expression was scored on examination under 40× magnification, with the incidence of cellular staining averaged over 10 high‐power fields. The intensity and extent of staining were characterized semiquantitatively using the standard World Health Organization classification criteria. The median follow‐up duration was approximately 5.5 years. Multivariate analyses were performed to ascertain the statistical significance of several standard clinicohistopatholgic factors (Karnofsky functional status, age, gender, extent of surgical resection, radiotherapy dose, grade, and PTHrP expression) with respect to local control and survival. P < 0.05 was considered indicative of statistical significance.RESULTSPatients with high levels of PTHrP expression had significantly lower glial tumor local control rates and corresponding decreases in progression‐free and overall actuarial survival after definitive irradiation (P < 0.01). In a Cox 3‐variable model, the PTHrP staining score was independent of tumor grade or Karnofsky functional status. It is notable that the strongest predictor of survival was tumor grade (P < 0.001).CONCLUSIONSPTHrP may be an important adjunct to standard immunopathologic criteria in the determination of glial tumor responses. A number of mechanisms were explored to derive a more mechanistic understanding of these translational results. Subsequent prospective studies involving larger patient populations will be necessary before findings can be translated to clinical practice. Cancer 2004. © 2004 American Cancer Society.

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Lead alters parathyroid hormone‐related peptide and transforming growth factor‐β1 effects and AP‐1 and NF‐κKB signaling in chondrocytes

Cited by 37 publications

References 48 publications

Regulation of chondrogenesis and chondrocyte differentiation by stress

Regulation of chondrogenesis and chondrocyte differentiation by stress

Allogeneic and Autogenous Bone Grafts Are Affected by Historical Donor Environmental Exposure

Parathyroid hormone–related protein expression is correlated with clinical course in patients with glial tumors

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