Adipose-derived leptin and complement factor D mediate osteoarthritis severity and pain

Obesity is a risk factor for osteoarthritis (OA), and leptin is among the adipokines implicated in obesity-induced OA. However, the specific role of leptin in OA severity and pain is not known. Using lipodystrophic (LD) mice, we show fat-secreted factors are required for knee OA development, implicating a fat-cartilage crosstalk. Fat pad implantation or systemic leptin restoration in LD mice reintroduced structural OA and pain, whereas implantation of leptin-deficient fat pad did not change OA susceptibility. Isochronic parabiosis and spatial transcriptomics confirmed that fat-joint crosstalk likely occurred via soluble mediators. Global unsupervised multiomics of conditioned media from fat implants revealed that leptin exerts a regulatory effect on adipsin (or complement factor D), the activity of which modulates contrastive OA structural and pain phenotype. These findings suggest adipokines influence OA pathogenesis, providing conclusive evidence of a fat-joint crosstalk and implicati..., Animal Studies
All experimental procedures were approved by the Washington University School of Medicine Department of Comparative Medicine Institutional Animal Care and Use Committee (WUSTL IACUC 22-0306) and were conducted in accordance with ARRIVE guidelines. LD mice and WT (DTA/+) littermate controls were generated for these studies by crossing adiponectin-Cre (Jackson Labs: 028020) mice with homozygous lox-stop-lox-ROSA-diphtheria toxin A (Jackson Labs: 010527) mice on a C57BL/6 background. To breed at mendelian frequency, mice were bred and maintained at thermoneutrality throughout their lifespan (30 °C). Mixed genotype mice were group-housed such that n = 3 to 5 per cage.
Male LD mice received either a MEF transplant (MEF-rescue) from WT, leptin heterozygous (MEF-HET) or leptin homozygous knockout (MEF-KO) pups as previously described, which developed into adipose-like tissue between 3 and 5 weeks of age. The injection was delivered subcutaneously to the sternal aspect ..., , # Adipose-derived leptin and complement factor D mediate osteoarthritis severity and pain

[https://doi.org/10.5061/dryad.dz08kps7c](https://doi.org/10.5061/dryad.dz08kps7c)

Co-Corresponding Author Information:
Name: Kelsey H. Collins
ORCID: 0000-0001-7348-7348
Institution: UCSF
Address: 35 Medical Center Way, RMB Pod C, San Francisco, Ca, 94941
Email: [[e-mail]](mailto:[e-mail])

Name: Farshid Guilak
ORCID: 0000-0001-7380-0330
Institution: Washington University in St. Louis
Address: 660 S. Euclid Ave, St. Louis, Mo, 63110
Email: [[e-mail]](mailto:[e-mail])

## Description of the data and file structure

This study investigates the role of systemic leptin and complement factor D secreted by adipose tissue in osteoarthritis and musculoskeletal pain in mice. Enclosed are the data for all figures in the paper except for the bulk RNA sequencing datasets. Please address questions to F. Guilak and K. Collins. These data were generated, collected,...,

肥胖是骨关节炎（Osteoarthritis, OA）的危险因素，而瘦素（leptin）是参与肥胖诱导型骨关节炎的脂肪因子（adipokines）之一。然而，瘦素在骨关节炎严重程度与疼痛中的具体作用仍未明确。本研究利用脂肪营养不良（lipodystrophic, LD）小鼠模型，证实脂肪分泌因子是膝关节骨关节炎发生的必需条件，提示存在脂肪-软骨串扰（fat-cartilage crosstalk）机制。向LD小鼠进行脂肪垫移植或全身性瘦素补充，可恢复其骨关节炎结构病变与疼痛表型；而移植瘦素缺陷型脂肪垫则不会改变小鼠的骨关节炎易感性。同年代射联体（isochronic parabiosis）实验与空间转录组学（spatial transcriptomics）分析证实，脂肪-关节串扰可能通过可溶性介质实现。对脂肪移植体的条件培养基进行全局无监督多组学（multiomics）分析后发现，瘦素可对脂肪酶（adipsin，又称补体因子D）发挥调控作用，而该因子的活性可调控骨关节炎结构病变与疼痛表型的差异表型。上述研究结果表明脂肪因子可影响骨关节炎的发病机制，为脂肪-关节串扰提供了确凿证据，并暗示……[动物实验]

所有实验流程均已通过华盛顿大学医学院比较医学系实验动物护理与使用委员会（WUSTL IACUC 22-0306）批准，并严格遵循ARRIVE指南开展。本研究通过将C57BL/6背景下的脂联素-Cre（adiponectin-Cre，杰克逊实验室货号：028020）小鼠与纯合lox-stop-lox-ROSA-白喉毒素A（lox-stop-lox-ROSA-diphtheria toxin A，杰克逊实验室货号：010527）小鼠杂交，获得LD小鼠与野生型（WT, DTA/+）同窝对照小鼠。为保证孟德尔式遗传频率，小鼠整个生命周期均在热中性环境（30℃）中繁育与饲养。混合基因型小鼠采用群居饲养方式，每笼饲养3~5只。

雄性LD小鼠分别接受野生型、瘦素杂合子（MEF-HET）或瘦素纯合子敲除（MEF-KO）幼鼠的胚胎成纤维细胞（MEF）移植（MEF rescue），移植后3~5周可形成脂肪样组织，具体操作如既往研究所述。移植方式为胸骨部位皮下注射……

# 脂肪来源瘦素与补体因子D调控骨关节炎严重程度与疼痛
DOI：10.5061/dryad.dz08kps7c

共同通讯作者信息：
姓名：凯尔西·H·柯林斯（Kelsey H. Collins）
ORCID：0000-0001-7348-7348
所属机构：加州大学旧金山分校（UCSF）
通讯地址：美国加利福尼亚州旧金山医疗中心大道35号RMB C舱，邮编94941
电子邮箱：[e-mail]

姓名：法希德·吉拉克（Farshid Guilak）
ORCID：0000-0001-7380-0330
所属机构：圣路易斯华盛顿大学
通讯地址：美国密苏里州圣路易斯市南欧几里德大道660号，邮编63110
电子邮箱：[e-mail]

数据与文件结构说明
本研究探讨了脂肪组织分泌的全身性瘦素与补体因子D在小鼠骨关节炎及肌肉骨骼疼痛中的作用。本数据集包含论文中除批量RNA测序数据集外的所有图表数据。相关问题请联系F. 吉拉克与K. 柯林斯。本数据集经生成、收集……