Table 3 Cellular/molecular effects of relaxin-relevant literature findings

Basic Properties of Relaxin

Goldsmith et al. 1995 [20]

Grossman et al. 2010 [32]

Lubahn et al. 2006 [4]

MacLennan et al. 1983 [13]

Powell et al. 2015 [14]

Wolf et al. 2012 [11]

Wolf et al. 2013 [15]

Relaxin (RLX^*) is a peptide hormone in the insulin-like growth factor (IGF^†) family

Men and women have similar serum levels (400–500 pg/mL and 360–495 pg/mL), with luteal phase peaks in women

Oral contraceptives decrease relaxin below a detectable serum level

The major gene for relaxin in humans is H2; H2 relaxin binds relaxin family peptide receptor 1 and 2

The corpus luteum produces most relaxin, but synthesis occurs in the endometrium, placenta, breast tissue, and prostate

Relaxin is biologically and immunologically active during pregnancy

The capacity of relaxin to act locally means that serum levels do not always reflect activity

Properties of Relaxin Receptors

Bryant-Greenwood et al. 1982 [25]

Dragoo et al. 2003 [11]

Kapila et al. 1998 [18]

Kleine et al. 2017 [33]

MacLennan et al. 1983 [13]

Powell et al. 2015 [14]

In humans, relaxin family peptide receptor-1 (RXFP^‡) is most common, and has the highest affinity for H2 relaxin

Relaxin binds receptors in a time-, temperature-, and pH-dependent manner

RXFP^‡ expression is primed by estrogen/progesterone in chondroblasts, fibrochondroblasts, myofibroblasts, and ligaments

Estrogen-primed receptors can show maximum response at RLX^* levels 10–100 times lower than normal

Estrogen, progesterone, and relaxin receptors modulate MMP^§ transcription and post-translational modification

Radioreceptor location detection is a sensitive indicator of the physiological roles of RLX^*

Relaxin receptors are detectable in anterior cruciate ligament (ACL^¶) remnants of female, but not male, surgical patients

RLX^* binding was uniform, saturable, and specific to the synovial lining, stromal fibroblasts, and intima

Relaxin receptors have been detected in the carpometacarpal joint of the thumb (1^st CMC^#) in arthroplasty patients

The synovial lining, dorsoradial ligament, volar oblique ligament, and articular cartilage cells had receptors

Concentration of RLX^* receptors was significantly higher in women compared to men

Relaxin receptors have been detected in the temporomandibular joint (TMJ^**), on fibrochondrocytes and ligaments

Functional, Physiologic Properties of Relaxin

Ando et al. 1960 [34]

Dragoo et al. 2003 [5]

Galey et al. 2003 [35]

Goldsmith et al. 1995 [20]

Grossman et al. 2010 [32]

Nose-Ogura et al. 2017 [21]

Powell et al. 2015 [14]

Relaxin controls extracellular matrix (ECM^††) turnover by stimulating collagen degradation, and suppressing synthesis

Relaxin upregulates MMP^¥ production, specifically collagenases (MMP-1/-13) and gelatinases (MMP^§-2/-9)

Active collagenases cleave tropocollagen, making it susceptible to subsequent denaturation by gelatinases

The density and organization of collagen bundles, and total local collagen content decrease

MMP^§s induced by relaxin degrade collagen at a nanoscale level, and macro-level effects are not always appreciable

Relaxin has dose-dependent and differential functioning; its effects depend on location and presence of other hormones

There is a significant correlation between peak serum relaxin and peak serum progesterone levels

Intracellular relaxin activates MAPK^‡‡ and PI3K^§§, increasing cAMP^¶¶ and triggering vasodilation via MMP^§-2/-9

Estrogen, progesterone, and relaxin binding synovial receptors upregulates inflammatory MMP^§s, increasing OA^## risk

Relaxin upregulates production of collagenases and gelatinases in ligaments and fibrocartilage

During parturition, relaxin binding pubic ligaments dissociates collagen, increases water uptake, and decreases viscosity