title: The effects of lactate and acid on articular chondrocytes function: Implications for polymeric cartilage scaffold design.
abstract: Poly (lactic-co-glycolic acid) (PLGA) and poly-l-lactate acid (PLLA) are biodegradable polymers widely utilized as scaffold materials for cartilage tissue engineering. Their acid degradation products have been widely recognized as being detrimental to cell function. However, the biological effects of lactate, rather than lactic acid, on chondrocytes have never been investigated. This is the major focus of this study. The amounts of lactate and the pH value (acid) of the PLGA and PLLA degradation medium were measured. The effects of PLGA and PLLA degradation medium, as well as different lactate concentrations and timing of exposure on chondrocytes proliferation and cartilage-specific matrix synthesis were investigated by various techniques including global gene expression profiling and gene knockdown experiments. It was shown that PLGA and PLLA degradation medium differentially regulated chondrocyte proliferation and matrix synthesis. Acidic pH caused by lactate inhibited chondrocyte proliferation and matrix synthesis. The effect of lactate on chondrocyte matrix synthesis was both time and dose dependent. A lactate concentration of 100mM and exposure duration of 8h significantly enhanced matrix synthesis. Lactate could also inhibit expression of cartilage matrix degradation genes in osteoarthritic chondrocytes, such as the major aggrecanase ADAMTS5, whilst promoting matrix synthesis simultaneously. Pulsed addition of lactate was shown to be more efficient in promoting COL2A1 expression. Global gene expression data and gene knock down experiments demonstrated that lactate promote matrix synthesis through up-regulation of HIF1A. These observed differential biological effects of lactate on chondrocytes would have implications for the future design of polymeric cartilage scaffolds.
  
  
  
  Lactic acid is a widely used substrate for polymers synthesis, PLGA and PLLA in particular. Although physical and biological modifications have been made on these polymers to make them be better cartilage scaffolds, little concern has been given on the biological effect of lactic acid, the main degradation product of these polymers, on chondrocytes. Our finding illustrates the differential biological function of lactate and acid on chondrocytes matrix synthesis. These results can facilitate future design of lactate polymers-based cartilage scaffolds.
authors.affiliation: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, China; Department of Orthopaedics, The Second Affiliated Hospital, Wenzhou Medical University, China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, China.
authors.forename: Xiaolei
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, China.
authors.forename: Yan
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, China; Department of Orthopaedics, The Second Affiliated Hospital, Wenzhou Medical University, China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, China.
authors.forename: Zongyou
authors.initials: Z
authors.lastname: Pan
authors.affiliation: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, China.
authors.forename: Heng
authors.initials: H
authors.lastname: Sun
authors.affiliation: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, China.
authors.forename: Junjuan
authors.initials: J
authors.lastname: Wang
authors.affiliation: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, China.
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Yu
authors.affiliation: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, China.
authors.forename: Shouan
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Dai
authors.affiliation: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, China.
authors.forename: Yishan
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Orthopaedics, The Second Affiliated Hospital, Wenzhou Medical University, China.
authors.forename: Naifeng
authors.initials: N
authors.lastname: Tian
authors.affiliation: Faculty of Dentistry, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Boon Chin
authors.initials: BC
authors.lastname: Heng
authors.affiliation: Point Loma Nazarene University, United States.
authors.forename: Noelle D
authors.initials: ND
authors.lastname: Coen
authors.affiliation: Department of Orthopaedics, The Second Affiliated Hospital, Wenzhou Medical University, China. Electronic address: spinexu@163.com.
authors.forename: Huazi
authors.initials: H
authors.lastname: Xu
authors.affiliation: Dr. Li Dak Sum & Yip Yio Chin Center for Stem Cells and Regenerative Medicine, School of Medicine, Zhejiang University, China; Key Laboratory of Tissue Engineering and Regenerative Medicine of Zhejiang Province, School of Medicine, Zhejiang University, China; Department of Sports Medicine, School of Medicine, Zhejiang University, China; State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, 310003 Hangzhou, China. Electronic address: hwoy@zju.edu.cn.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Ouyang
mesh_terms: D002358:Cartilage, Articular / Q000166:cytology*; D049109:Cell Proliferation / Q000187:drug effects; D019902:Chondrocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D005109:Extracellular Matrix / Q000187:drug effects / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D019344:Lactic Acid / Q000737:chemistry / Q000494:pharmacology*; D010003:Osteoarthritis / Q000235:genetics / Q000473:pathology; D011100:Polyglycolic Acid / Q000737:chemistry*; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D013997:Time Factors; D054457:Tissue Scaffolds / Q000737:chemistry*
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid
keywords: Chondrocyte; Lactate; Polymeric cartilage scaffold