Table 1.

Recent studies exploring potential regulators of enzymatic collagen crosslinking in tendon, ligament, and related tissues.

Potential regulator	Species/tissue	Age/time point	Treatment	Evaluation	Major findings	Source
Mechanical stimuli	Chick tendon	HH 28-HH 45, tendon explant cultured for 48 h	Paralysis, hypermotility, BAPN	Mechanical testing, LOX/LOXL expression and activity	Paralysis (unloading) decreases modulus and LOX activity, LOXL isoforms respond uniquely to mechanical loading	Pan et al., 2018
	Human-derived periodontal ligament cells	24 or 48 h culture	3 % or 10 % mechanical stretch	RT-PCR, fluorescence imaging	3 % stretch promotes LOX and collagen production whereas 10 % stretch upregulates MMP2 expression with no changes to LOX activity	Chen et al., 2016
	Human-derived periodontal ligament cells, rat periodontal ligament	12 or 24 h culture, 3 d of treatment	Compressive loading, excessive occlusal loading	LOX/LH2/collagen gene expression, tissue histology	Low loading increases LOX/LH2 expression, excessive occlusal loading increases collagen maturation and LOX/LH2 expression	Kaku et al., 2016
	Rat tail tendon, mouse tail tendon	14–18 weeks (rat), 10–39 weeks (mouse)	PIEZO1 gain (or loss) of function	Mechanical testing, calcium imaging, crosslink analyses	PIEZO1 affects enzymatic crosslinking density and crosslinking appears to be mechanosensitive	Passini et al., 2021
Hypoxia	Bovine patellar tendon and articular cartilage	4–8 weeks old bovine tissue explant cultured for 4 weeks	Hypoxia, exogenous LOXL2	Mechanical testing, LOX expression, crosslink analyses	Increased number of mature crosslinks, increased LOX expression (evaluated in articular cartilage only), and increased modulus with hypoxia and LOXL2 treatment	Makris et al., 2014
TGFβ signaling	Human trabecular meshwork cells	24 h treatment in culture	Exogenous TGFβ, inhibitors of TGFβ signaling	RT-PCR, Western blot	TGFβ1-3 isoforms promote LOX and LOXL1-4 expression through canonical and non-canonical TGFβ signaling pathways	Sethi et al., 2011
	Human trabecular meshwork cells	24 h treatment in culture	BMP antagonist, inhibitors of TGFβ signaling	LOX/LOXL1-4 expression	BMP antagonist gremlin induces LOX and LOXL expression through TGFβ signaling	Sethi et al., 2013
Protein interactions	Mouse dermis, human-derived fibroblasts	8 weeks old, 24–96 h culture	TSP-1 knockout	Solid-phase binding assays, fluorescence imaging	TSP-1 binds to intracellular and extracellular collagen and interacts with dermal LOX activity	Rosini et al., 2018
	Mouse tail tendon	5 months old	Fibromodulin knockout	Solid phase proximity ligation assay, histology	Fibromodulin interacted with LOX at the surface of collagen fibrils	Kalamajski et al., 2016
	Mouse tail tendon	2 months old	Cyp B knockout	TEM imaging, mass spectrometry, histology	Cyp B knockout impairs tendon fibrillogenesis; altered lysine hydroxylation	Terajima et al., 2016
Estrogen	Human ACL-derived fibroblasts	20–24 year old fibroblasts cultured for 14 d	Exogenous estradiol, BAPN	Mechanical testing, hydroxyproline assay, LOX activity assay	Estrogen reduces tissue engineered construct mechanical properties and LOX activity	Lee et al., 2015