Wenhan Chang, PhD
Professor
Medicine
School of Medicine

We study mice with conditional knockout (KO) of genes encoding CaSR, GABBR1, IGF1, IGF1R, PTH1R, Cyp27b1, FGF23, Klotho, VDR, and their associated signaling molecules in parathyroid cells (PTC), intestinal epithelial cells, renal tubule cells, chondrocytes, bone cells, and/or neurons to determine their biological functions. These in vivo studies are complemented with in vitro cell/organ cultures of parathyroid cells/glands; primary intestinal and renal tubular cells and associated cell lines; primary chondrocyte, osteoblast, osteoclast, and related cell lines; and neurons to further delineate the underlying mechanisms. We perform union and nonunion bone fractures on the above KO mice and study the structural, biochemical, and biomechanics properties of the resulting callus to determine the functions of the CaSR, GABBR1, IGF1, IGF1R, PTH1R, Cyp27b1, VDR, and their associated signaling molecules in fracture healing. Based on the above study, we are developing new pharmacological regimens for more robust skeletal anabolism to treat osteoporosis and to repair bone. We also perform brain ischemia and traumatic brain injury protocols on the KO mice to assess the role of those molecules in the development of neuronal injury and to develop new therapies for neuroprotection against ischemia- and TBI-induced brain injury. Dr. Chang is also the director of the SF-VAMC Bone Imaging Core facility.

• Precise druggability of the PTH type 1 receptor.
  Nature chemical biology 2021 Sutkeviciute I, Lee JY, White AD, Maria CS, Peña KA, Savransky S, Doruker P, Li H, Lei S, Kaynak B, Tu C, Clark LJ, Sanker S, Gardella TJ, Chang W, Bahar I, Vilardaga JP
• Spatial bias in cAMP generation determines biological responses to PTH type 1 receptor activation.
  Science signaling 2021 White AD, Peña KA, Clark LJ, Maria CS, Liu S, Jean-Alphonse FG, Lee JY, Lei S, Cheng Z, Tu CL, Fang F, Szeto N, Gardella TJ, Xiao K, Gellman SH, Bahar I, Sutkeviciute I, Chang W, Vilardaga JP
• FBW7 couples structural integrity with functional output of primary cilia.
  Communications biology 2021 Petsouki E, Gerakopoulos V, Szeto N, Chang W, Humphrey MB, Tsiokas L
• The mTORC2 Regulator Homer1 Modulates Protein Levels and Sub-Cellular Localization of the CaSR in Osteoblast-Lineage Cells.
  International journal of molecular sciences 2021 Rybchyn MS, Brennan-Speranza TC, Mor D, Cheng Z, Chang W, Conigrave AD, Mason RS
• Enhanced excitability of cortical neurons in low-divalent solutions is primarily mediated by altered voltage-dependence of voltage-gated sodium channels.
  eLife 2021 Martiszus BJ, Tsintsadze T, Chang W, Smith SM
• Calcium-sensing receptor and CPAP-induced neonatal airway hyperreactivity in mice.
  Pediatric research 2021 Mayer CA, Roos B, Teske J, Wells N, Martin RJ, Chang W, Pabelick CM, Prakash YS, MacFarlane PM
• Renal Dnase1 expression is regulated by FGF23 but loss of Dnase1 does not alter renal phosphate handling.
  Scientific reports 2021 Egli-Spichtig D, Zhang MYH, Li A, Pastor Arroyo EM, Hernando N, Wagner CA, Chang W, Perwad F
• Calcium-sensing receptor-mediated NLRP3 inflammasome response to calciprotein particles drives inflammation in rheumatoid arthritis.
  Nature communications 2020 Jäger E, Murthy S, Schmidt C, Hahn M, Strobel S, Peters A, Stäubert C, Sungur P, Venus T, Geisler M, Radusheva V, Raps S, Rothe K, Scholz R, Jung S, Wagner S, Pierer M, Seifert O, Chang W, Estrela-…
• Control of PTH secretion by the TRPC1 ion channel.
  JCI insight 2020 Onopiuk M, Eby B, Nesin V, Ngo P, Lerner M, Gorvin CM, Stokes VJ, Thakker RV, Brandi ML, Chang W, Humphrey MB, Tsiokas L, Lau K
• PTH hypersecretion triggered by a GABAB1 and Ca2+-sensing receptor heterocomplex in hyperparathyroidism.
  Nature metabolism 2020 Chang W, Tu CL, Jean-Alphonse FG, Herberger A, Cheng Z, Hwong J, Ho H, Li A, Wang D, Liu H, White AD, Suh I, Shen W, Duh QY, Khanafshar E, Shoback DM, Xiao K, Vilardaga JP
• Glycerol-3-phosphate is an FGF23 regulator derived from the injured kidney.
  The Journal of clinical investigation 2020 Simic P, Kim W, Zhou W, Pierce KA, Chang W, Sykes DB, Aziz NB, Elmariah S, Ngo D, Pajevic PD, Govea N, Kestenbaum BR, de Boer IH, Cheng Z, Christov M, Chun J, Leaf DE, Waikar SS, Tager AM, Gerszten RE…
• Calcium-Sensing Receptors in Chondrocytes and Osteoblasts Are Required for Callus Maturation and Fracture Healing in Mice.
  Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2019 Cheng Z, Li A, Tu CL, Maria CS, Szeto N, Herberger A, Chen TH, Song F, Wang J, Liu X, Shoback DM, Chang W
• Phosphate acts directly on the calcium-sensing receptor to stimulate parathyroid hormone secretion.
  Nature communications 2019 Centeno PP, Herberger A, Mun HC, Tu C, Nemeth EF, Chang W, Conigrave AD, Ward DT
• Homer1 mediates CaSR-dependent activation of mTOR complex 2 and initiates a novel pathway for AKT-dependent β-catenin stabilization in osteoblasts.
  The Journal of biological chemistry 2019 Rybchyn MS, Islam KS, Brennan-Speranza TC, Cheng Z, Brennan SC, Chang W, Mason RS, Conigrave AD
• Myosin 1a Regulates Osteoblast Differentiation Independent of Intestinal Calcium Transport.
  Journal of the Endocrine Society 2019 Munson S, Wang Y, Chang W, Bikle DD
• Prevention of Injury-Induced Osteoarthritis in Rodent Temporomandibular Joint by Targeting Chondrocyte CaSR.
  Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2019 Zhang M, Yang H, Wan X, Lu L, Zhang J, Zhang H, Ye T, Liu Q, Xie M, Liu X, Yu S, Guo S, Chang W, Wang M
• The calcium-sensing receptor in physiology and in calcitropic and noncalcitropic diseases.
  Nature reviews. Endocrinology 2018 Hannan FM, Kallay E, Chang W, Brandi ML, Thakker RV
• Calcium-Sensing Receptor Regulates Epidermal Intracellular Ca2+ Signaling and Re-Epithelialization after Wounding.
  The Journal of investigative dermatology 2018 Tu CL, Celli A, Mauro T, Chang W
• Calcimimetic R568 inhibits tetrodotoxin-sensitive colonic electrolyte secretion and reduces c-fos expression in myenteric neurons.
  Life sciences 2017 Sun X, Tang L, Winesett S, Chang W, Cheng SX
• Cartilage to bone transformation during fracture healing is coordinated by the invading vasculature and induction of the core pluripotency genes.
  Development (Cambridge, England) 2017 Hu DP, Ferro F, Yang F, Taylor AJ, Chang W, Miclau T, Marcucio RS, Bahney CS
• Calcium-Sensing Receptor Promotes Breast Cancer by Stimulating Intracrine Actions of Parathyroid Hormone-Related Protein.
  Cancer research 2016 Kim W, Takyar FM, Swan K, Jeong J, VanHouten J, Sullivan C, Dann P, Yu H, Fiaschi-Taesch N, Chang W, Wysolmerski J
• Sprouty2 regulates endochondral bone formation by modulation of RTK and BMP signaling.
  Bone 2016 Joo A, Long R, Cheng Z, Alexander C, Chang W, Klein OD
• Calcium Sensing Receptor Function Supports Osteoblast Survival and Acts as a Co-Factor in PTH Anabolic Actions in Bone.
  Journal of cellular biochemistry 2016 Al-Dujaili SA, Koh AJ, Dang M, Mi X, Chang W, Ma PX, McCauley LK
• Unilateral anterior crossbite induces aberrant mineral deposition in degenerative temporomandibular cartilage in rats.
  Osteoarthritis and cartilage 2015 Zhang M, Wang H, Zhang J, Zhang H, Yang H, Wan X, Jing L, Lu L, Liu X, Yu S, Chang W, Wang M
• Interplay between CaSR and PTH1R signaling in skeletal development and osteoanabolism.
  Seminars in cell & developmental biology 2015 Santa Maria C, Cheng Z, Li A, Wang J, Shoback D, Tu CL, Chang W
• Comparative expression of the extracellular calcium-sensing receptor in the mouse, rat, and human kidney.
  American journal of physiology. Renal physiology 2015 Graca JA, Schepelmann M, Brennan SC, Reens J, Chang W, Yan P, Toka H, Riccardi D, Price SA
• The vascular Ca2+-sensing receptor regulates blood vessel tone and blood pressure.
  American journal of physiology. Cell physiology 2015 Schepelmann M, Yarova PL, Lopez-Fernandez I, Davies TS, Brennan SC, Edwards PJ, Aggarwal A, Graça J, Rietdorf K, Matchkov V, Fenton RA, Chang W, Krssak M, Stewart A, Broadley KJ, Ward DT, Price SA, …
• Role of IGF-I signaling in muscle bone interactions.
  Bone 2015 Bikle DD, Tahimic C, Chang W, Wang Y, Philippou A, Barton ER
• Osteoblast-Specific Loss of IGF1R Signaling Results in Impaired Endochondral Bone Formation During Fracture Healing.
  Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2015 Wang T, Wang Y, Menendez A, Fong C, Babey M, Tahimic CG, Cheng Z, Li A, Chang W, Bikle DD
• Calcium-sensing receptor antagonists abrogate airway hyperresponsiveness and inflammation in allergic asthma.
  Science translational medicine 2015 Yarova PL, Stewart AL, Sathish V, Britt RD, Thompson MA, P Lowe AP, Freeman M, Aravamudan B, Kita H, Brennan SC, Schepelmann M, Davies T, Yung S, Cholisoh Z, Kidd EJ, Ford WR, Broadley KJ, Rietdorf K,…
• Calcium-sensing receptor stimulates Cl(-)- and SCFA-dependent but inhibits cAMP-dependent HCO3(-) secretion in colon.
  American journal of physiology. Gastrointestinal and liver physiology 2015 Tang L, Peng M, Liu L, Chang W, Binder HJ, Cheng SX
• The calcium-sensing receptor suppresses epithelial-to-mesenchymal transition and stem cell- like phenotype in the colon.
  Molecular cancer 2015 Aggarwal A, Prinz-Wohlgenannt M, Gröschel C, Tennakoon S, Meshcheryakova A, Chang W, Brown EM, Mechtcheriakova D, Kállay E
• Wnt5a/Ror2 mediates temporomandibular joint subchondral bone remodeling.
  Journal of dental research 2015 Yang T, Zhang J, Cao Y, Zhang M, Jing L, Jiao K, Yu S, Chang W, Chen D, Wang M
• Calcium-sensing receptor (CaSR) as a novel target for ischemic neuroprotection.
  Annals of clinical and translational neurology 2014 Kim JY, Ho H, Kim N, Liu J, Tu CL, Yenari MA, Chang W
• Ephrin B2/EphB4 mediates the actions of IGF-I signaling in regulating endochondral bone formation.
  Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2014 Wang Y, Menendez A, Fong C, ElAlieh HZ, Chang W, Bikle DD
• Disrupted bone remodeling leads to cochlear overgrowth and hearing loss in a mouse model of fibrous dysplasia.
  PloS one 2014 Akil O, Hall-Glenn F, Chang J, Li A, Chang W, Lustig LR, Alliston T, Hsiao EC
• Joint instability and cartilage compression in a mouse model of posttraumatic osteoarthritis.
  Journal of orthopaedic research : official publication of the Orthopaedic Research Society 2013 Onur TS, Wu R, Chu S, Chang W, Kim HT, Dang AB
• Autocrine and Paracrine Actions of IGF-I Signaling in Skeletal Development.
  Bone research 2013 Wang Y, Bikle DD, Chang W
• Hypothermia and pharmacological regimens that prevent overexpression and overactivity of the extracellular calcium-sensing receptor protect neurons against traumatic brain injury.
  Journal of neurotrauma 2013 Kim JY, Kim N, Yenari MA, Chang W
• Mammary-specific ablation of the calcium-sensing receptor during lactation alters maternal calcium metabolism, milk calcium transport, and neonatal calcium accrual.
  Endocrinology 2013 Mamillapalli R, VanHouten J, Dann P, Bikle D, Chang W, Brown E, Wysolmerski J
• Sex and age modify biochemical and skeletal manifestations of chronic hyperparathyroidism by altering target organ responses to Ca2+ and parathyroid hormone in mice.
  Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2013 Cheng Z, Liang N, Chen TH, Li A, Santa Maria C, You M, Ho H, Song F, Bikle D, Tu C, Shoback D, Chang W
• The extracellular calcium-sensing receptor, CaSR, in fetal development.
  Best practice & research. Clinical endocrinology & metabolism 2013 Riccardi D, Brennan SC, Chang W
• Ablation of the calcium-sensing receptor in keratinocytes impairs epidermal differentiation and barrier function.
  The Journal of investigative dermatology 2012 Tu CL, Crumrine DA, Man MQ, Chang W, Elalieh H, You M, Elias PM, Bikle DD
• Osteoblast extracellular Ca2+ -sensing receptor regulates bone development, mineralization, and turnover.
  Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2011 Dvorak-Ewell MM, Chen TH, Liang N, Garvey C, Liu B, Tu C, Chang W, Bikle DD, Shoback DM
• Negative cross-talk between calcium-sensing receptor and β-catenin signaling systems in colonic epithelium.
  The Journal of biological chemistry 2011 Rey O, Chang W, Bikle D, Rozengurt N, Young SH, Rozengurt E
• IGF-1R signaling in chondrocytes modulates growth plate development by interacting with the PTHrP/Ihh pathway.
  Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 2011 Wang Y, Cheng Z, Elalieh HZ, Nakamura E, Nguyen MT, Mackem S, Clemens TL, Bikle DD, Chang W
• Mild Hypothermia Suppresses Calcium-Sensing Receptor (CaSR) Induction Following Forebrain Ischemia While Increasing GABA-B Receptor 1 (GABA-B-R1) Expression.
  Translational stroke research 2011 Kim JY, Kim N, Yenari MA, Chang W
• The calcium-sensing receptor-dependent regulation of cell-cell adhesion and keratinocyte differentiation requires Rho and filamin A.
  The Journal of investigative dermatology 2011 Tu CL, Chang W, Bikle DD
• Naturally-occurring mutation in the calcium-sensing receptor reveals the significance of extracellular domain loop III region for class C G-protein-coupled receptor function.
  The Journal of clinical endocrinology and metabolism 2010 Dong Q, Cheng Z, Chang W, Blackman BE, Conte FA, Hu J, Shoback D, Miller WL
• Assessing constitutive activity of extracellular calcium-sensing receptors in vitro and in bone.
  Methods in enzymology 2010 Chang W, Dvorak M, Shoback D
• The extracellular calcium-sensing receptor (CaSR) is a critical modulator of skeletal development.
  Science signaling 2008 Chang W, Tu C, Chen TH, Bikle D, Shoback D
• Inactivation of the calcium sensing receptor inhibits E-cadherin-mediated cell-cell adhesion and calcium-induced differentiation in human epidermal keratinocytes.
  The Journal of biological chemistry 2007 Tu CL, Chang W, Xie Z, Bikle DD
• Type B gamma-aminobutyric acid receptors modulate the function of the extracellular Ca2+-sensing receptor and cell differentiation in murine growth plate chondrocytes.
  Endocrinology 2007 Cheng Z, Tu C, Rodriguez L, Chen TH, Dvorak MM, Margeta M, Gassmann M, Bettler B, Shoback D, Chang W
• Complex formation with the Type B gamma-aminobutyric acid receptor affects the expression and signal transduction of the extracellular calcium-sensing receptor. Studies with HEK-293 cells and neurons.
  The Journal of biological chemistry 2007 Chang W, Tu C, Cheng Z, Rodriguez L, Chen TH, Gassmann M, Bettler B, Margeta M, Jan LY, Shoback D
• Constitutive activity of the osteoblast Ca2+-sensing receptor promotes loss of cancellous bone.
  Endocrinology 2007 Dvorak MM, Chen TH, Orwoll B, Garvey C, Chang W, Bikle DD, Shoback DM
• The role of the calcium sensing receptor in regulating intracellular calcium handling in human epidermal keratinocytes.
  The Journal of investigative dermatology 2006 Tu CL, Chang W, Bikle DD
• WITHDRAWN: Type B gamma-aminobutyric Acid Receptors Modulate the Expression and Function of the Extracellular Ca2+-sensing Receptor in Murine Growth Plate Chondrocytes.
  Endocrinology 2006 Cheng Z, Tu C, Rodriguez L, Dvorak MM, Margeta M, Gassmann M, Bettler B, Shoback D, Chang W
• Insulin-like growth factor-I is essential for embryonic bone development.
  Endocrinology 2006 Wang Y, Nishida S, Sakata T, Elalieh HZ, Chang W, Halloran BP, Doty SB, Bikle DD
• Expression and functional assessment of an alternatively spliced extracellular Ca2+-sensing receptor in growth plate chondrocytes.
  Endocrinology 2005 Rodriguez L, Tu C, Cheng Z, Chen TH, Bikle D, Shoback D, Chang W
• Extracellular calcium and parathyroid hormone-related peptide signaling modulate the pace of growth plate chondrocyte differentiation.
  Endocrinology 2005 Rodriguez L, Cheng Z, Chen TH, Tu C, Chang W
• Phospholipase cgamma1 is required for activation of store-operated channels in human keratinocytes.
  The Journal of investigative dermatology 2005 Tu CL, Chang W, Bikle DD
• Extracellular Ca2+-sensing in cartilage.
  Journal of musculoskeletal & neuronal interactions 2004 Chang W, Rodriguez L, Chen TH, Tu C, Shoback D
• cDNA cloning and functional expression of a Ca2+-sensing receptor with truncated C-terminal tail from the Mozambique tilapia (Oreochromis mossambicus).
  The Journal of biological chemistry 2004 Loretz CA, Pollina C, Hyodo S, Takei Y, Chang W, Shoback D
• Extracellular Ca2+-sensing receptors--an overview.
  Cell calcium 2004 Chang W, Shoback D
• Epidermal expression of the full-length extracellular calcium-sensing receptor is required for normal keratinocyte differentiation.
  Journal of cellular physiology 2002 Komuves L, Oda Y, Tu CL, Chang WH, Ho-Pao CL, Mauro T, Bikle DD
• Extracellular Ca(2+)-sensing receptors modulate matrix production and mineralization in chondrogenic RCJ3.1C5.18 cells.
  Endocrinology 2002 Chang W, Tu C, Pratt S, Chen TH, Shoback D
• Amino acids in the cytoplasmic C terminus of the parathyroid Ca2+-sensing receptor mediate efficient cell-surface expression and phospholipase C activation.
  The Journal of biological chemistry 2001 Chang W, Pratt S, Chen TH, Bourguignon L, Shoback D
• Starvation amidst plenty--rickets and hypercalcemia in calcium receptor knockout mice.
  Endocrinology 2001 Shoback D, Chang W
• The extracellular calcium-sensing receptor is required for calcium-induced differentiation in human keratinocytes.
  The Journal of biological chemistry 2001 Tu CL, Chang W, Bikle DD
• Parathyroid cells express dihydropyridine-sensitive cation currents and L-type calcium channel subunits.
  American journal of physiology. Endocrinology and metabolism 2001 Chang W, Pratt SA, Chen TH, Tu CL, Mikala G, Schwartz A, Shoback D
• Cloning and characterization of human WDR10, a novel gene located at 3q21 encoding a WD-repeat protein that is highly expressed in pituitary and testis.
  DNA and cell biology 2001 Gross C, De Baere E, Lo A, Chang W, Messiaen L
• Amino acids in the second and third intracellular loops of the parathyroid Ca2+-sensing receptor mediate efficient coupling to phospholipase C.
  The Journal of biological chemistry 2000 Chang W, Chen TH, Pratt S, Shoback D
• The calcium sensing receptor and its alternatively spliced form in murine epidermal differentiation.
  The Journal of biological chemistry 2000 Oda Y, Tu CL, Chang W, Crumrine D, Kömüves L, Mauro T, Elias PM, Bikle DD
• Protein kinase C activation blocks calcium receptor signaling in Xenopus laevis oocytes.
  Molecular and cellular endocrinology 1999 Chang W, Pratt S, Chen TH, Shoback D
• Expression and signal transduction of calcium-sensing receptors in cartilage and bone.
  Endocrinology 1999 Chang W, Tu C, Chen TH, Komuves L, Oda Y, Pratt SA, Miller S, Shoback D
• Calcium sensing in cultured chondrogenic RCJ3.1C5.18 cells.
  Endocrinology 1999 Chang W, Tu C, Bajra R, Komuves L, Miller S, Strewler G, Shoback D
• Regulation of extracellular calcium-activated cation currents by cAMP in parathyroid cells.
  The American journal of physiology 1998 Chang W, Chen TH, Pratt S, Shoback D
• Coupling of calcium receptors to inositol phosphate and cyclic AMP generation in mammalian cells and Xenopus laevis oocytes and immunodetection of receptor protein by region-specific antipeptide antisera.
  Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 1998 Chang W, Pratt S, Chen TH, Nemeth E, Huang Z, Shoback D
• Parathyroid Ca(2+)-conducting currents are modulated by muscarinic receptor agonists and antagonists.
  The American journal of physiology 1997 Chang W, Chen TH, Pratt SA, Yen B, Fu M, Shoback D
• [Acute hepatic porphyria and its neurological syndrome].
  Schweizerische medizinische Wochenschrift 1996 Bont A, Steck AJ, Meyer UA
• Regulation of Ca(2+)-conducting currents in parathyroid cells by extracellular Ca(2+) and channel blockers.
  The American journal of physiology 1995 Chang W, Chen TH, Gardner P, Shoback D
• DPC blockade of transepithelial chloride absorption and single anion channels in teleost urinary bladder.
  The American journal of physiology 1993 Chang W, Loretz CA
• Identification of a stretch-activated monovalent cation channel from teleost urinary bladder cells.
  The Journal of experimental zoology 1991 Chang WH, Loretz CA